Table of Contents Author Guidelines Submit a Manuscript
Neural Plasticity
Volume 2014 (2014), Article ID 723915, 14 pages
http://dx.doi.org/10.1155/2014/723915
Review Article

Hippocampal Neurogenesis and Antidepressive Therapy: Shocking Relations

1Paracelsus Medical University, Institute of Experimental Neuroregeneration, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Strubergasse 22, 5020 Salzburg, Austria
2Paracelsus Medical University, Institute of Molecular Regenerative Medicine, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Strubergasse 22, 5020 Salzburg, Austria
3University Clinics of Psychiatry and Psychotherapy I, Paracelsus Medical University, Ignaz-Harrer-Straße 79, 5020 Salzburg, Austria

Received 31 January 2014; Accepted 25 April 2014; Published 22 May 2014

Academic Editor: Paul Lucassen

Copyright © 2014 Peter Rotheneichner et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Speculations on the involvement of hippocampal neurogenesis, a form of neuronal plasticity, in the aetiology of depression and the mode of action of antidepressive therapies, started to arise more than a decade ago. But still, conclusive evidence that adult neurogenesis contributes to antidepressive effects of pharmacological and physical therapies has not been generated yet. This review revisits recent findings on the close relation between the mode(s) of action of electroconvulsive therapy (ECT), a powerful intervention used as second-line treatment of major depression disorders, and the neurogenic response to ECT. Following application of electroconvulsive shocks, intricate interactions between neurogenesis, angiogenesis, and microglia activation, the hypothalamic-pituitary-adrenal axis and the secretion of neurotrophic factors have been documented. Furthermore, considering the fact that neurogenesis strongly diminishes along aging, we investigated the response to electroconvulsive shocks in young as well as in aged cohorts of mice.

1. Electroconvulsive Therapy and Major Depression Disorders

Major depression is one of the most common forms of mental disorders in humans. Hereditary and environment-triggered forms of this disease lead to a severe decline of life quality and might elicit life-threating events like suicide attempts. Despite the constant development and improvement of antidepressive drugs, a compound providing fast and long-lasting pharmacological efficacy in most patients is still lacking. Although the binding specificity for recently developed drug-classes, for example, selective serotonin noradrenalin reuptake inhibitors (SSNRIs), has been improved further, concerns regarding their side effects, such as the increased risk of suicide, must be heeded.

Electroconvulsive therapy (ECT) as an alternative treatment offers a safe, rapid, and potent therapy to severely depressed patients. ECT-associated side effects, like cognitive impairments, are transient and may slightly vary from one ECT-protocol to the other [1, 2]. ECT was firstly performed by Ugo Cerletti and Lucio Bini in 1938 [3] and induces rapid improvements on mental disorders. In contrast, standard pharmacological antidepressive treatments, such as the administration of selective serotonin reuptake inhibitors (SSRIs), commonly show their first efficacy weeks after initiation and are dependent on individual features such as sex, treatment, or disease pattern [4, 5]. Since the introduction of ECT in the clinic, several parameters, such as electrode placement, pulse width, and pulse shape were improved in order to optimize efficacy and minimize side effects [68]. Nowadays, ECT has several indications, for instance, psychotic and melancholic depressions, malignant catatonia, and delirious mania [9]. Nevertheless, ECT is predominantly used in severe cases of major depression as a second line treatment following failure of pharmacological approaches [10]. Overall, according to meta-analyses of clinical studies ECT was reported to be significantly more effective in depressive disorders compared to pharmacological treatments [2, 11].

2. Are Neurogenesis and Antidepressive Activity Linked?

Adult neurogenesis, the generation of new neurons, takes place in numerous mammalian species, including humans [12, 13]. Neurogenesis occurs in at least two specific areas of the adult brain, namely, the dentate gyrus of the hippocampus and the subventricular zone (SVZ) of the lateral ventricles. In these so-called neurogenic niches, neural stem cells (NSCs) can on the one hand divide symmetrically, leading to two daughter stem cells and on the other hand perform an asymmetric division resulting in a daughter stem cell and a rapid amplifying progenitor cell. Depending on the microenvironment and surrounding factors, these progenitor cells can, over a period of three to four weeks in rodents, mature into neurons which integrate into existing neuronal networks. Along aging, the number of neural stem and progenitor cells declines significant and various steps of neurogenesis (e.g., proliferation, survival, or maturation) get decelerated [1416]. The cause for the decreased levels of proliferation in old individuals is still under debate. Putative mechanisms could lengthen cell cycles, deplete progenitor cells in the hippocampus, or cause their quiescence [14]. Additionally, events such as depression or stress strongly reduce the hippocampal potential for plasticity [17]. Environmental changes, however, can counteract this decline by stimulating neurogenesis and probably lead to healthy aging [18, 19].

To elucidate the mechanisms by which ECT leads to antidepressive effects, preclinical research has primarily made use of experimental electroconvulsive shock (ECS), the animal model counterpart of ECT. A strong enhancement of neurogenesis has been observed in various species following experimental ECS treatments [20, 21]. Several studies indicated a close relation between hippocampal function and mood regulation. The observation of an antidepressive-like effect and an upregulation of hippocampal cell proliferation upon experimental ECS raised speculations on the participation of neurogenesis in the antidepressive mode of action. However, evidence for a direct participation of neurogenesis in antidepressive mechanisms still remains to be convincingly demonstrated [17].

Based on various correlations observed in experimental ECS animal studies, several hypotheses like the stimulation of neurogenesis, the restoration of hippocampal volume, modulations of neurotransmitter and hormone levels, changes in angiogenesis, and cerebral blood flow have been formulated to account for the antidepressive action of ECT. In this report, we revisited the impact of experimental ECS on neurogenesis and speculate on the mechanisms leading to its upregulation, which may be also involved in ECT’s antidepressive effects in patients. Moreover, the influence of aging on the impact of ECT/experimental ECS and neurogenesis has been scrutinized in more detail.

3. Enhanced Neurogenesis following Antidepressive Treatment: Effect or Side Effect of the Therapy?

Numerous groups reported a close relation between adult born hippocampal neurons and antidepressive effects [22]. Chronic administration of antidepressants, which counteract the negative behavioural effects of chronic stress, leads reportedly to an upregulation of neurogenesis [23]. Additionally evidence supporting the involvement of neurogenesis in the mode of antidepressant action has subsequently been revealed by Santarelli and colleagues, showing that deletion of neurogenesis in mice via hippocampal X-ray irradiation ablated the behavioural response to the antidepressants imipramine and fluoxetine [24]. However, further experiments displayed that the ablation of hippocampal neurogenesis per se does not elicit a depressive phenotype [2528]. Besides, it could be shown by Sah and colleagues, using a mouse model of increased anxiety, that rather the levels of neuronal activity in the dentate gyrus than the rates of neurogenesis correlate with the depression-like behaviours [29].

To evaluate studies addressing experimental ECS working mechanisms, it is noteworthy that most studies have been performed in healthy animals and only occasionally in animal models based on chronic stress. These situations certainly differ from the complex conditions pertaining in patients with mental disorders like major depression. Despite this, biological effects of experimental ECS on the central nervous system (CNS) in animals can be monitored properly. Taken together, the accumulated evidence suggests that depression does not result from an impaired neurogenesis but that the addition of new neurons in the hippocampal circuitry may facilitate the action of antidepressants.

It is intriguing that the delayed behavioural response to common antidepressant drugs, for example, SSRIs, in rodents coincides with the delayed upregulation of neurogenesis, that is, after approximately three weeks [30]. Similarly, the rapid antidepressive action of experimental ECS is associated with a rapid stimulation of neurogenesis, which follows after the first treatment [31]. In this context, the enlargement of the immature neuron population may be involved in the behavioural response. These immature cells have been demonstrated to be highly excitable compared to mature neurons [32]. Therefore, stimulation by lower input intensity could lead to a higher input sensitivity of the whole surrounding network.

Nonetheless, one should not get the impression out of these speculations that depression is exclusively a hippocampal disorder. The involvement of additional cerebral structures, such as the amygdala, the frontal cortex, and the thalamus, has been well documented in studies revealing structural abnormalities and disbalances of neurotransmitters [3335]. Hence, ECT is likely to act on numerous cerebral structures, possibly stimulating their neuronal plasticity. In this respect, pharmacological antidepressive treatments were shown to restore the mechanism of long term potentiation (LTP) [36, 37], which is impaired in depressed patients and animal models with depressive-like behaviours. As previously demonstrated for pharmacological treatments, ECT might stop dendritic atrophy [38, 39] or increase dendritic spine density in various cortical and limbic structures [40, 41]. In the hippocampus, plasticity is not restricted to synaptic plasticity but also involves cellular plasticity, that is, neurogenesis. As mentioned above, an enhanced number of immature neurons may increase excitability of the hippocampus and putatively associated areas of the limbic system as well. Alternatively or in addition, ECT might rewire existing neuronal networks, for example, via sprouting of mossy fibers, that is, axonal projections of the granular neurons to the CA3 pyramidal neurons in the hippocampus, restoring thereby functionality of limbic and cortical circuits. Although it remains to be definitely demonstrated that upregulation of neurogenesis contributes to the antidepressive action, levels of neurogenesis could become a surrogate marker to predict and monitor the patients’ response to treatment. Even though adequate protocols for in vivo measurement of human neurogenesis are not existent yet, efforts have been recently deployed using magnetic resonance spectroscopy (MRS) [42, 43] and positron emission tomography (PET) using labelled tracer [44].

4. Differences in ECS and Pharmacological Treatment on Neural Stem Cells

The finding that experimental ECS strongly induces hippocampal neurogenesis in various mammals, including rodents and nonhuman primates, triggered the idea of using ECS to modulate the pool of neural stem and progenitor cells. Pharmacological antidepressive treatments, like fluoxetine administration, act mainly on amplifying neural progenitors (ANPs) [45]. In contrast, it has been postulated that experimental ECS can in addition shove quiescent neural progenitors (QNPs) from their resting phase to a proliferative status, thereby increasing the pool of active stem cells generating new progenitor cells [46, 47] (Figure 1). Importantly, new neurons generated upon experimental ECS-treatment do not differ in fate or phenotype as compared to neurons generated under physiological conditions [31]. Hence, new neurons generated following experimental ECS mature and integrate in the existing neuronal network and form appropriate synapses [48, 49].

723915.fig.001
Figure 1: Differentiation and maturation of adult neural stem cells. The process from stem cell division to the fully integrated mature neuron in the dentate gyrus takes approximately 30 days in rodents. Specific markers characterize the various maturation stages (e.g., DCX for neuroblasts). Experimental ECS or pharmacological treatments can influence neurogenesis at various stages; experimental ECS is also reported to activate quiescent stem cells.

5. Age-Dependent Response to ECT

To date, most experimental ECS studies were performed in young animals, even though depressive episodes must be addressed also in aged individuals. As a group, in which major depression disorders are increased and often underdiagnosed, the elderly could especially benefit from ECT. On the one hand, this population is often poly-medicated, which increases the risk of adverse drug interaction upon additional pharmacological interventions. On the other hand, ECT offers an alternative to classical pharmacological antidepressants, which fail as first line treatment in the aged population in up to 77% [50]. This lack of response to antidepressant drugs might be exacerbated by age-related physiological changes, such as decreased concentrations of acetylcholine and dopamine, increased level of monoamine oxidase activity, or increased concentration of cortisol due to a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis [50]. Remarkably, repeated ECT treatments have shown to be as effective as pharmacological antidepressive therapy in avoiding relapse in aged individuals [51]. Nevertheless, both pharmacological and ECT-based approaches benefit from a multimodal therapy concept complemented by physical and mental exercises, psychological therapy, and resocialisation.

So far, the mechanisms by which experimental ECS and antidepressant drugs interfere with cells of the neurogenic niches could not be fully deciphered. Both types of antidepressive treatments have been reported to increase the number of proliferating cells in the hippocampus and promote the maturation of neuronal progenitors [5, 20, 30, 52]. Under our experimental ECS paradigm, we could demonstrate a highly significant increase of cell proliferation in the dentate gyrus of mice from the young and aged groups (for details please see section Material and Methods) (Figure 2). In the 20-month-old mice, ECS increased the number of BrdU-labelled cells by more than sixfold as compared to the aged sham-treated mice, whereas in the 2-month-old mice the increase was roughly a doubling. Most of the BrdU+ cells were located in the subgranular zone of the dentate gyrus, the place where neural stem cells are resident. Intriguingly, those BrdU+ cells in the 20-month-old group expressed neither Nestin, a marker for neural stem cells, nor Doublecortin (DCX), a marker for neuronal progenitors. It is possible that in aged individuals the maturation steps from stem cells and early progenitors to immature neurons expressing DCX are slowed down. Further studies need to address kinetics and fate of newly generated cells after experimental ECS, especially in aged individuals.

fig2
Figure 2: Representative micrographs showing the detection of BrdU-labelled cells in the dentate gyrus of a 2-month-old mouse from (a) the sham group or (b) the experimental ECS group. Scale bar: 200 μm. (c) The number of BrdU+ cells was determined to estimate the rates of cell proliferation in the dorsal DG of 2- and 20-month-old mice. Both groups showed a highly significant enhancement in cell proliferation following experimental ECS-treatment. Two months, (); 20 months, ().

6. How Neurogenesis May Be Supported by Modulation of Microenvironment

Neural stem and progenitor cells are embedded in a complex cellular niche with tight regulatory interactions between the different cellular partners. Not only is this microenvironment exposed to factors delivered by the blood system but also stem and progenitor cells are in close contact with cells forming and surrounding the blood vessels such as pericytes and astrocytes [15, 53]. This organization referred to as the neurovascular unit is involved in the precise regulation of neurogenesis [54]. It is well documented that endothelial cells, astrocytes, and microglia modulate the behaviour of stem and progenitor cells [5557]. The impact of experimental ECS on these cell populations was therefore examined. In mice and nonhuman primates, histological staining revealed that experimental ECS increases the expression level of GFAP as well as the number of cells expressing this astrocyte marker in the hippocampus [20, 47, 58]. In our own experiments, we focused on GFAP+ cells in the granular layer of the dentate gyrus of 2- and 20-month-old mice. Overall, experimental ECS-treatment increases the expression of GFAP significantly (Figure 3). A detailed analysis of our data showed an age dependent effect of this treatment; hence, only the 2-month-old group of mice showed a significant increase of GFAP-expression. Some recent studies demonstrated that GFAP-expressing cells in the cortex could be triggered to become multipotent neural progenitors [59]. It remains to be elucidated if experimental ECS and ECT can recruit a pool of quiescent progenitors within the hippocampus and thereby increase neurogenesis.

fig3
Figure 3: Detection of GFAP in the dentate gyrus of (a) sham-treated or (b) ECS-treated mouse of the 2 months of age cohort, scale bar in (a) 100 μm. (c) Graph showing percentage of area covered by GFAP-expressing cells in the granular layer of dentate gyrus in 2- and 20-month-old mice following ECS or sham treatment. A two-way ANOVA detected a significant increase of the GFAP expression upon experimental ECS ( ()). Bonferroni post hoc test revealed that the significance resulted from differences in the 2-month-old group ().

Microglia, the immune cells of the CNS, have been shown to influence neurogenesis [60]. Within the granular layer in the dentate gyrus of young and old mice we detected cells, expressing the ionized calcium-binding adaptor molecule 1 (Iba1), a marker for microglia cells. With our experimental setup, we observed no increase in the amount of Iba1+ cells in the dentate gyrus (2 months: sham  cells/mm3 versus ECS  cells/mm3  ; 20 months: sham  cells/mm3 versus ECS  cells/mm3  ); however, the experimental ECS enhanced the volume of Iba1+ cells significantly (Figure 4). These enlarged microglia, namely, hyper-ramified, constitute an intermediate state between resting and activated [61]. Such enlarged microglia have been previously reported to appear after experimental ECS-treatment in rodents [62]. Furthermore, Jansson et al. reported an upregulation of MHCII in microglia following experimental ECS, which also suggests an activation of these immune cells. The group proposed that these MHCII-expressing microglia play a significant role for maintenance of neurogenesis in the hippocampus. Taken together, these observations indicate that experimental ECS modulates the microglial activation state to the benefit of neurogenesis and therefore potentially contributes also to the antidepressive effect.

fig4
Figure 4: (a) Detection of microglia in the granular layer (GL) of a 2-month-old mouse based on the expression of Iba1 (white) (ML: molecular layer). Scale bar: 50 μm. (b) Microglia volume was estimated according to the percentage of the surface covered by Iba1+ labelling in the granular layer of 2- and 20-month-old mice following ECS or sham treatment. Two-way ANOVA revealed upon ECS a significant increase of Iba1-labeled surface in the dentate gyrus of both age groups ().

7. Blood System and Its Role in ECT

The antidepressive action of ECT can most likely not be reduced to a single mechanism, but results from the synergistic cooperation of several processes and factors involving neurogenesis, modulation of blood supply and angiogenesis, corticosteroids, brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and so forth. Indeed, a closer look at these putative modes of action reveals close interconnection between the different systems. For instance, proliferation of stem cells located in the neurogenic niches can be modulated by factors delivered via the closely associated vasculature [63]. In aged mice, we showed that neurogenesis is downregulated by blood derived signalling molecules that are delivered through the vessels. However, neurogenesis can be reactivated by the introduction of young blood into the circulation via direct serum injection or heterochronic parabiosis [64].

Considering that neurogenic niches are closely apposed on blood vessels delivering nutrients and numerous factors, it is noteworthy that comorbidities between cardiovascular diseases and depression have been reported in numerous studies (e.g., see [65, 66]). Moreover, PET imaging revealed that ECT treatment transiently changes local cerebral blood flow, leading to an increase in the brain stem, diencephalon and basal ganglia for instance [67]. Yet, the so-called blood-brain barrier (BBB) constitutes a barrier controlling the molecular exchange between the circulating blood and the brain parenchyma (reviewed, e.g., by Ilbay and colleagues [68]). Roughly speaking, the BBB prevents under physiological conditions the diffusion of large and/or hydrophilic molecules but allows for the passage of hydrophobic molecules and substances having their specific transporters, for example, glucose. Neuropathological disturbances like stroke or epileptic seizure, can lead to leakage of this barrier [68]. Under these conditions, various circulating molecules can diffuse out of the blood vessels and thereby change the microenvironment of the brain parenchyma and of the neurogenic niches.

It has been proposed that experimental ECS leads to a greater permeability of the BBB, enabling an influx of blood-derived factors into the parenchyma. However, leakage of the BBB has not been observed as an acute effect of experimental ECS but was rather seen following several experimental ECS sessions in rodent models [69]. For instance, no increased permeability to Evans Blue was reported by Oztas and collaborators following a single experimental ECS treatment; however, BBB leakage could be recognized after ten experimental ECS-sessions [70]. The potential BBB leakage after ECT was furthermore analysed in humans using different tracers for PET imaging by Bolwig and colleagues, who concluded that, due to changes in local cerebral blood flow and potentially from the leakage of newly formed capillaries, proteins could pass more easily out of the blood vessels following ECT [71]. In a subsequent study on the experimental ECS-induced BBB leakage in rats, Sartorius and colleagues reported elevated BDNF levels in the serum as well as the prefrontal cortex and the hippocampus after five experimental ECS sessions. According to their hypothesis, a fraction of the parenchymal BDNF originated from the blood circulation and crossed the BBB after experimental ECS [72]. Hence, enhanced BBB permeability might contribute to the beneficial impact of repeated ECT session, yet the rapid induction of neurogenesis seen after a single experimental ECS session is unlikely linked to an early failure of the BBB integrity.

Strikingly, Hattiangady and colleagues reported that the number of neural stem cells in the dentate gyrus is not decreasing with age, but only their activation state, which was shown to be closely dependant on the distance of stem cells to the next blood vessel [73]. Therefore, experimental ECS might upregulate neurogenesis by promoting a closer association of stem cells to the blood vessels. Angiogenesis, the generation of new blood vessels, is tightly regulated during development and in the adult brain by numerous factors in a similar fashion to neurogenesis [74]. In the healthy brain, the density of blood vessels remains relatively stable during adulthood [75]. However, increased angiogenesis (and neurogenesis) was observed in SSRI-treated patients suffering from major depression [74]. Similarly, experimental ECS treatment was reported to promote the elongation of existing vessels and to increase their density in the stratum lacunosum moleculare (SLM), a subregion of the hippocampal molecular layer [76, 77]. However, within the granular layer of the dentate gyrus, that is, in the vicinity of stem and progenitor cell somas, we did not detect an increase of the blood vessel density upon experimental ECS treatments (Figure 5). Nevertheless, an enhanced vascularization in the molecular layer could intensify the delivery factors to the tip of radial stem cells or to the dendritic trees of granular neurons for retrograde transport and signalling. Alternatively, factors secreted in the molecular layer could act on other cells types capable of neurogenesis modulation, for example, astrocytes and microglia. Furthermore, Newton et al. proposed that endothelial cells per se can influence neurogenesis by secreting factors acting on neural stem and progenitor cells [77].

fig5
Figure 5: (a) Detection of blood vessels in the granular layer of the dorsal dentate gyrus with B. simplicifolia lectin (red) (inset, overview of the dentate gyrus with position of the field of view, ML: molecular layer, GL: granular layer). Scale bar: 50 μm. (b) No significant differences in blood vessel density could be detected following ECS. Interestingly, aged brains had a slightly decreased vessel density compared to the younger group ().

8. Neurogenesis and the Normalisation of the HPA-Axis

The crosstalk between neurogenesis and the ECT putative modes of action is further exemplified by the modulation of the hypothalamic-pituitary-adrenal-axis (HPA-axis) signalling during depression and its interaction with the neurogenesis [7881]. In depressed patients, the regulation of the HPA-axis is heavily disturbed. The malfunction of the negative feedback mechanisms results in an excessive secretion of the hormone cortisol. Interestingly, increased levels of cortisol and defective HPA-axis response were also reported in aged individuals [82]. In general, the level of glucocorticoids negatively correlates with the proliferation rates of neural stem and progenitor cells which possess the receptors for glucocorticoid and mineralocorticoids [83, 84]. Surget and colleagues established an important link between neurogenesis and the antidepressive effect of fluoxetine by identifying a direct correlation between newly generated neurons and the restoration of adequate control on the HPA stress response system [85]. The report demonstrated namely that the generation of new neurons is required for the function of the negative feedback loop of the HPA-axis, while others critically discuss a direct correlation [86]. Interestingly, high levels of cortisol have also antiangiogenic properties [87]. Long-lasting elevated cortisol levels, such as in the aged individual, have been proposed to induce epigenetic alterations in neural stem and progenitor cells, which could lead to their long term quiescence and therefore to a significant reduction of neurogenesis [88].

Preclinical research on experimental ECS has been performed often in young and healthy animals, which do not show signs of depressive behaviour. For a better understanding of the processes taking place in the depressed brain and the impact of ECT on the CNS, adequate animal models showing depressive-like behaviour with elevated corticosteroid-levels should be selected. This could be achieved artificially by direct injection of corticosteroids. Application of large doses of corticosteroids was reported to inhibit neurogenesis in a rat model. In this model, cell proliferation in the dentate gyrus could be restored to physiological levels by experimental ECS treatment [89]. Hence, experimental ECS may be indirectly involved in the normalization of the HPA-axis regulation through the activation of neurogenesis.

9. Release of Signalling Factors following Experimental ECS and ECT

In animal models, experimental ECS activates additionally neurons of the hypothalamic-pituitary-system, namely, the paraventricular nucleus, supraoptic nucleus, and ventromedial nucleus (PVN, SON, and VMH), which regulate the secretion of diverse depression-relevant HPA-axis-related hormones, such as adrenocorticotropin, neuropeptide Y (NPY), prolactin, and vasopressin [62, 9094]. It has been reported that NPY concentrations were decreased in the cerebrospinal fluid (CSF) of depressed patients, but through ECT treatments the level could be normalized again [9597]. The link between NPY and depression was further validated in rodents, in which a direct administration of NPY into the lateral cerebral ventricles led to an antidepressive effect [94].

In addition to the modulation of HPA-related neuropeptides, experimental ECS treatment leads to higher concentration of several neurogenic/neurotrophic factors like BDNF, VEGF, neuritin, nerve growth factor (NGF), and fibroblast growth factor 2 (FGF2) within the CNS [46, 98100]. A stronger secretion of these factors and the induction of cell proliferation can be observed even after a single experimental ECS; however, the proliferation level will further increase with multiple experimental ECS sessions [21, 101, 102]. The biological activities of factors induced by experimental ECS are manifold. For instance the neurotrophic factor neuritin, which is one of the most upregulated genes in the granule cell layer of the dentate gyrus following experimental ECS, induces neurite outgrowth [103]. Other upregulated factors, like FGF-2, possess mitogenic, neurotrophic, and neuroprotective capabilities [104]. Finally, VEGF, besides being one of the most potent angiogenic factors, also promotes neurogenesis after experimental ECS [46, 63, 105, 106].

Importantly, experimental ECS treatments increase the levels of BDNF in areas of the brain relevant to depression, such as the entorhinal cortex and the hippocampus [99, 107]. The observation that the infusion of BDNF into the midbrain or hippocampus led to an antidepressive effect substantiated the role of BDNF in experimental ECS mode of action [108, 109]. BDNF was also shown to increase synaptic strength, neuronal survival, and integration but not the proliferation [110, 111]. In animal models receiving chronic administration of antidepressant drugs, the appearance of the antidepressive activity coincided with the increase of BDNF concentrations and relied on TrkB-signalling [112]. Interestingly, secretion of proBDNF, the precursor of mature BDNF, was increased in rat hippocampal synaptosomes even after one experimental ECS session and could be further enhanced by repeated sessions [113].

The neurogenic impact of BDNF not only is dependent on its net concentration in the brain but also is determined by the BDNF subtypes expressed. BDNF has at least 34 different transcripts, which can be translated to mature forms of BDNF [114]. Alternative and age dependent regulation in various brain regions and involvement of BDNF in diverse functions complicated the analysis of BDNF signalling [115]. It is noteworthy that a polymorphic variant of BDNF (G169A) might associate with major depression and carriers of this polymorphism were observed to have a reduced hippocampal volume. Nevertheless, these individuals do not differ in their response to ECT in comparison to other depressed patients [116].

10. Gain of Hippocampal Volume following Experimental ECS and ECT

Several studies pointed out a significant hippocampal atrophy in depressed patients and animal models of depression [117121]. This decline of hippocampal volume could be directly correlated with the duration of untreated depression [120]. Postmortem studies revealed that the hippocampal volume reduction originated from a reduction of neuronal volume and of the glial density [122124]. Nevertheless, a normal hippocampal volume could be regained following ECT-treatment of depressed patients [125]. Interestingly, the hippocampal volume could also be significantly increased by ECS session in nondepressed rodent and non-human primate models [20].

As mentioned above, the brains of young and old differ in several aspects, including changes in neurotransmitter concentrations, decline of stem and progenitor cell proliferation, or alterations of hormone levels. In our experiments, experimental ECS treatments could slightly, but significantly, increase the volume of the dentate gyrus of the younger cohort of mice (Figure 6). In the 20-month-old mice the volume increase failed to reach significance. Hence, the mechanisms leading to the volumetric changes following experimental ECS appear to be dampened with ageing, which may disclose a reduced plasticity and correlate with the higher rates of depression recurrence observed in the elderly population [126]. Although the validity of volumetric measurements as a biomarker for the monitoring of depression remains to be established, the rapid volumetric response to experimental ECS treatment may reflect the responsiveness of mechanisms controlling plasticity of the brain.

fig6
Figure 6: (a) Overview of a murine hippocampus with its substructures cornu ammonis (CA) 1–3, lateral ventricle (LV), stratum lacunosum moleculare (SLM), molecular layer (ML), granular layer (GL), and the hilus. Scale bar: 200 μm. (b) Volume of the dorsal dentate gyrus of 2- and 20-month-old mice following ECS or sham-treatment. Young mice showed a significant increase of volume after ECS (2 months, (); 20 months (ns)).

11. Epilepsy and Experimental ECS/ECT-Induced Plasticity

ECT shares some similarities with epileptic seizures, for instance, a massive excitation of neuronal networks and an enhanced cell proliferation in dentate gyrus. It is noteworthy that experimental ECS, in contrast to epileptic seizures, results neither in neurotoxicity and apoptosis, nor in the appearance of ectopic neurons in the hilus of the hippocampus [21, 76]. A proper wiring between the dentate gyrus and its target area, namely, the CA3, is important for correct processing of information entering the hippocampal circuitry. This connectivity has been reported to be aberrant in the brains of patients suffering of temporal lobe epilepsy or following experimental seizures in rodents [127]. On the other hand, experimental ECS sessions promote sprouting of mossy fibers without generation of abnormal connectivity and therefore do not lead to the appearance of spontaneous epileptic activities [128, 129]. This is in clear contrast with the stimulation of hippocampal neurogenesis through epileptic seizures, which results in the generation of new neurons characterized by structural and functional abnormalities [130].

The addition of new neurons and rewiring of hippocampal networks likely contribute to the antidepressive activity of experimental ECS, although the mechanisms are still to be elucidated. Recent evidence suggests that the antidepressive effect is not proportional to the number of newly generated neurons but rather to the activation of the whole neuronal population [86]. Substantiating this hypothesis is the observation that c-fos, a marker for cellular activity, is strongly upregulated in mature neurons of the dentate gyrus after experimental ECS [110]. Sah and colleagues further reported that the antidepressive effects of fluoxetine in a mouse model of anxiety disorder resulted from the restoration of the hypoactive dentate gyrus back to a normal activity level and not from an elevation of the neurogenesis rate [29]. Nevertheless, taken that newly generated neurons are significantly more excitable than their mature counterparts, increasing neurogenesis may also result in the increase of global dentate gyrus activity [32, 131, 132].

12. Outlook

There is still an important debate on the antidepressive mode of actions of ECT, but undoubtedly this treatment is a fast and powerful therapy with few side effects and, simultaneously, a very potent enhancer of hippocampal neurogenesis. Even a decade after the report that antidepressants increase the rate of hippocampal neurogenesis, relation between the latter and the antidepressive activity could not be fully deciphered. Nevertheless, evidence for a functional relevance of adult hippocampal neurogenesis in processes of neuronal plasticity and behaviours is slowly emerging.

13. Material and Methods

In the experiment described in this review, we involved C57Bl/6 mice of two and twenty months of age in order to reflect the various age groups receiving antidepressive treatments. Number of mice were 11 (sham) and 11 (ECS) in the 2-month-old group and 8 (sham) and 9 (ECS) in the 20-month-old group, male and female equally distributed. Experiments were performed in conformity with the Directive (2010/63/EU) of the European Parliament and of the Council and were approved by the local animal health commission. Animals were bred in the central animal facility of the Paracelsus Medical University, Salzburg, Austria. All animals were housed under standard conditions of a 12-hour light/dark cycle with food and water ad libitum.

These mice were submitted to a daily session of experimental ECS for five consecutive days. Anaesthesia right before shock application was obtained using 2.5% isoflurane in pure oxygen. ECS parameters applied were as follows: frequency 100 pulses/sec, pulse width 0.3 ms, shock duration 1 sec, and current 18 mA using an Ugo Basil 57800 ECT Unit via ear clips moisten with Ringer’s Solution. Sham-treated mice were only anaesthetized daily with isoflurane. In addition, dividing cells were marked by intraperitoneally BrdU injection (50 mg/kg bodyweight) daily at the end of every ECS or sham treatment.

For histological analysis, mice were perfused intracardially on day 6 with phosphate buffered 4% paraformaldehyde pH7.4. Thereafter, brains were further post-fixed overnight in the same solution and then cryoprotected with a 30% sucrose solution for several days. Brains were cut sagittal into 40 μm thick sections using a sliding microtome on dry ice (Leica, Nußloch Germany).

Immunohistological analyses were performed as previously described [133] using the following antibodies and kits: dividing cells were labelled with rat anti-BrdU (1:500, Serotec, Puchheim, Germany) and detected with a biotin-conjugated rabbit anti-rat (1:1000, Vector, Burlingame USA) followed by the VECTASTAIN ABC System and DAB Peroxidase Substrate kit (Vector, Burlingame USA). Microglia were labelled with rabbit anti-Iba1 (1:300, Wako, Neuss Germany) and detected with donkey anti-rabbit Alexa 647 (1:1000, Milipore, Billerica USA). For blood-vessel staining, biotinylated Lectin (1:500, Sigma-Aldrich, Vienna Austria) from B. simplicifolia was used followed by Streptavidin Alexa 488 (1:400, Invitrogen, Lofer Austria). Nuclei in fluorescence stainings were marked with 4′,6-diamidino-2-phenylindole (DAPI 0.5 μg/mL, Sigma-Aldrich, Vienna Austria).

Extrapolation for one brain hemisphere of the total number of BrdU or Iba1-labelled cells located in the dentate gyrus was performed by detection of BrdU in every tenth section or Iba1 in 3 randomly selected fields of view. Pictures were acquired with an Olympus IX81 (Olympus, Vienna Austria) microscope using the Volocity Software (Perkin Elmer).

The surface labelled with anti-GFAP, anti-Iba1, or Lectin was estimated as previously described [134, 135]. Briefly, z-stack pictures with a resolution of pixels covering the whole 40 μm slice were acquired using a LSM 700 confocal microscope (Carl Zeiss, Jena, Germany) with a 20x objective and Zeiss ZEN 2011 software. Stacks were merged using ImageJ Software 1.46r (National Institutes of Health, USA). The granular layer of dentate gyrus was outlined and converted to grey scale (Adobe Photoshop CS2, Adobe, San Jose USA) prior to the selection of a detection threshold. The percentage of pixels containing labelling within the dentate gyrus was quantified.

For statistical analysis, GraphPad Prism 5.0 (GraphPad Software Inc.) was used with two-tailed two-way ANOVA and Bonferroni post hoc test. Graphs show mean values with standard deviation as error bars. Significance was , , and .

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Acknowledgments

This work has been made possible through the support from the State Government of Salzburg (Austria), the foundation Propter Homines (Liechtenstein), and the FWF Special Research Program (SFB) F44 “Cell Signaling in Chronic CNS Disorders.” The research leading to these results has received funding from the European Union’s Seventh Framework Programme for research, technological development and, demonstration under Grant agreement no. 279288 (IDEA) and no. 278850 (INMiND). We acknowledge the support of the Core Facility Microscopy at SCI-TReCS.

References

  1. A. Ingram, M. M. Saling, and I. Schweitzer, “Cognitive side effects of brief pulse electroconvulsive therapy: a review,” Journal of ECT, vol. 24, no. 1, pp. 3–9, 2008. View at Publisher · View at Google Scholar · View at Scopus
  2. T. U. E. Group, “Efficacy and safety of electroconvulsive therapy in depressive disorders: a systematic review and meta-analysis,” The Lancet, vol. 361, no. 9360, pp. 799–808, 2003. View at Publisher · View at Google Scholar · View at Scopus
  3. T. Baghai, R. Frey, S. Kasper, and H.-J. Möller, Elektrokonvulsionstherapie: Klinische und Wissenschaftliche Aspekte, vol. 483, Springer, Vienna, Austria, 2004.
  4. J. R. Epp, C. L. Beasley, and L. A. Galea, “Increased hippocampal neurogenesis and p21 expression in depression: dependent on antidepressants, sex, age, and antipsychotic exposure,” Neuropsychopharmacology, vol. 38, no. 11, pp. 2297–2306, 2013. View at Google Scholar
  5. S. Couillard-Despres, C. Wuertinger, M. Kandasamy et al., “Ageing abolishes the effects of fluoxetine on neurogenesis,” Molecular Psychiatry, vol. 14, no. 9, pp. 856–864, 2009. View at Publisher · View at Google Scholar · View at Scopus
  6. B. Cronholm and J. O. Ottosson, “Ultrabrief stimulus technique in electroconvulsive therapy. II. Comparative studies of therapeutic effects and memory disturbances in treatment of endogenous depression with the elther es electroshock apparatus and siemens konvulsator III,” The Journal of Nervous and Mental Disease, vol. 137, pp. 268–276, 1963. View at Google Scholar · View at Scopus
  7. L. R. Squire and P. C. Slater, “Bilateral and unilateral ECT: effects on verbal and nonverbal memory,” American Journal of Psychiatry, vol. 135, no. 11, pp. 1316–1320, 1978. View at Google Scholar · View at Scopus
  8. L. R. Squire and J. A. Zouzounis, “ECT and memory: brief pulse versus sine wave,” American Journal of Psychiatry, vol. 143, no. 5, pp. 596–601, 1986. View at Google Scholar · View at Scopus
  9. M. Fink, “Electroconvulsive therapy resurrected: its successes and promises after 75 years,” Canadian Journal of Psychiatry, vol. 56, no. 1, pp. 3–4, 2011. View at Google Scholar · View at Scopus
  10. C. Salzman, E. Wong, and B. C. Wright, “Drug and ECT treatment of depression in the elderly, 1996–2001: a literature review,” Biological Psychiatry, vol. 52, no. 3, pp. 265–284, 2002. View at Publisher · View at Google Scholar · View at Scopus
  11. S. Sarkar and S. Grover, “A systematic review and meta-analysis of trials of treatment of depression from India,” Indian Journal of Psychiatry, vol. 56, no. 1, pp. 29–38, 2014. View at Google Scholar
  12. P. S. Eriksson, E. Perfilieva, T. Björk-Eriksson et al., “Neurogenesis in the adult human hippocampus,” Nature Medicine, vol. 4, no. 11, pp. 1313–1317, 1998. View at Publisher · View at Google Scholar · View at Scopus
  13. I. Amrein, K. Isler, and H.-P. Lipp, “Comparing adult hippocampal neurogenesis in mammalian species and orders: influence of chronological age and life history stage,” European Journal of Neuroscience, vol. 34, no. 6, pp. 978–987, 2011. View at Publisher · View at Google Scholar · View at Scopus
  14. E. Drapeau and D. N. Abrous, “Stem cell review series: role of neurogenesis in age-related memory disorders,” Aging Cell, vol. 7, no. 4, pp. 569–589, 2008. View at Publisher · View at Google Scholar · View at Scopus
  15. C. J. Miranda, L. Braun, Y. Jiang et al., “Aging brain microenvironment decreases hippocampal neurogenesis through Wnt-mediated survivin signaling,” Aging Cell, vol. 11, no. 3, pp. 542–552, 2012. View at Publisher · View at Google Scholar · View at Scopus
  16. V. M. Heine, S. Maslam, M. Joëls, and P. J. Lucassen, “Prominent decline of newborn cell proliferation, differentiation, and apoptosis in the aging dentate gyrus, in absence of an age-related hypothalamus-pituitary-adrenal axis activation,” Neurobiology of Aging, vol. 25, no. 3, pp. 361–375, 2004. View at Publisher · View at Google Scholar · View at Scopus
  17. P. J. Lucassen, M. W. Stumpel, Q. Wang, and E. Aronica, “Decreased numbers of progenitor cells but no response to antidepressant drugs in the hippocampus of elderly depressed patients,” Neuropharmacology, vol. 58, no. 6, pp. 940–949, 2010. View at Publisher · View at Google Scholar · View at Scopus
  18. G. Kempermann, H. G. Kuhn, and F. H. Gage, “Experience-induced neurogenesis in the senescent dentate gyrus,” Journal of Neuroscience, vol. 18, no. 9, pp. 3206–3212, 1998. View at Google Scholar · View at Scopus
  19. H. G. Kuhn, H. Dickinson-Anson, and F. H. Gage, “Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation,” Journal of Neuroscience, vol. 16, no. 6, pp. 2027–2033, 1996. View at Google Scholar
  20. T. D. Perera, J. D. Coplan, S. H. Lisanby et al., “Antidepressant-induced neurogenesis in the hippocampus of adult nonhuman primates,” Journal of Neuroscience, vol. 27, no. 18, pp. 4894–4901, 2007. View at Publisher · View at Google Scholar · View at Scopus
  21. T. M. Madsen, A. Treschow, J. Bengzon, T. G. Bolwig, O. Lindvall, and A. Tingström, “Increased neurogenesis in a model of electroconvulsive therapy,” Biological Psychiatry, vol. 47, no. 12, pp. 1043–1049, 2000. View at Publisher · View at Google Scholar · View at Scopus
  22. A. J. Eisch and D. Petrik, “Depression and hippocampal neurogenesis: a road to remission?” Science, vol. 338, no. 6103, pp. 72–75, 2012. View at Publisher · View at Google Scholar · View at Scopus
  23. R. S. Duman, S. Nakagawa, and J. Malberg, “Regulation of adult neurogenesis by antidepressant treatment,” Neuropsychopharmacology, vol. 25, no. 6, pp. 836–844, 2001. View at Publisher · View at Google Scholar · View at Scopus
  24. L. Santarelli, M. Saxe, C. Gross et al., “Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants,” Science, vol. 301, no. 5634, pp. 805–809, 2003. View at Publisher · View at Google Scholar · View at Scopus
  25. K. A. Holick, D. C. Lee, R. Hen, and S. C. Dulawa, “Behavioral effects of chronic fluoxetine in BALB/cJ mice do not require adult hippocampal neurogenesis or the serotonin 1A receptor,” Neuropsychopharmacology, vol. 33, no. 2, pp. 406–417, 2008. View at Publisher · View at Google Scholar · View at Scopus
  26. C. Zhao, W. Deng, and F. H. Gage, “Mechanisms and functional implications of adult neurogenesis,” Cell, vol. 132, no. 4, pp. 645–660, 2008. View at Publisher · View at Google Scholar · View at Scopus
  27. A. Sahay and R. Hen, “Adult hippocampal neurogenesis in depression,” Nature Neuroscience, vol. 10, no. 9, pp. 1110–1115, 2007. View at Publisher · View at Google Scholar · View at Scopus
  28. P. Jedynak, P. Jaholkowski, G. Wozniak, C. Sandi, L. Kaczmarek, and R. K. Filipkowski, “Lack of cyclin D2 impairing adult brain neurogenesis alters hippocampal-dependent behavioral tasks without reducing learning ability,” Behavioural Brain Research, vol. 227, no. 1, pp. 159–166, 2012. View at Publisher · View at Google Scholar · View at Scopus
  29. A. Sah, C. Schmuckermair, S. B. Sartori et al., “Anxiety- rather than depression-like behavior is associated with adult neurogenesis in a female mouse model of higher trait anxiety- and comorbid depression-like behavior,” Translational psychiatry, vol. 2, article e171, 2012. View at Google Scholar · View at Scopus
  30. J. E. Malberg, A. J. Eisch, E. J. Nestler, and R. S. Duman, “Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus,” Journal of Neuroscience, vol. 20, no. 24, pp. 9104–9110, 2000. View at Google Scholar · View at Scopus
  31. K. Nakamura, M. Ito, Y. Liu, T. Seki, T. Suzuki, and H. Arai, “Effects of single and repeated electroconvulsive stimulation on hippocampal cell proliferation and spontaneous behaviors in the rat,” Brain Research, vol. 1491, pp. 88–97, 2013. View at Publisher · View at Google Scholar · View at Scopus
  32. S. Couillard-Despres, B. Winner, C. Karl et al., “Targeted transgene expression in neuronal precursors: watching young neurons in the old brain,” European Journal of Neuroscience, vol. 24, no. 6, pp. 1535–1545, 2006. View at Publisher · View at Google Scholar · View at Scopus
  33. G. Sanacora, G. F. Mason, D. L. Rothman et al., “Increased cortical GABA concentrations in depressed patients receiving ECT,” American Journal of Psychiatry, vol. 160, no. 3, pp. 577–579, 2003. View at Publisher · View at Google Scholar · View at Scopus
  34. J. J. Mann, “Neurobiological correlates of the antidepressant action of electroconvulsive therapy,” Journal of ECT, vol. 14, no. 3, pp. 172–180, 1998. View at Google Scholar · View at Scopus
  35. M. Markianos, J. Hatzimanolis, and L. Lykouras, “Relationship between prolactin responses to ECT and dopaminergic and serotonergic responsivity in depressed patients,” European Archives of Psychiatry and Clinical Neuroscience, vol. 252, no. 4, pp. 166–171, 2002. View at Google Scholar · View at Scopus
  36. W. Li, L. Liu, Y.-Y. Liu et al., “Effects of electroconvulsive stimulation on long-term potentiation and synaptophysin in the hippocampus of rats with depressive behavior,” Journal of ECT, vol. 28, no. 2, pp. 111–117, 2012. View at Publisher · View at Google Scholar · View at Scopus
  37. K. G. Bath, D. Q. Jing, I. Dincheva et al., “BDNF Val66Met impairs fluoxetine-induced enhancement of adult hippocampus plasticity,” Neuropsychopharmacology, vol. 37, no. 5, pp. 1297–1304, 2012. View at Publisher · View at Google Scholar · View at Scopus
  38. J. M. Bessa, D. Ferreira, I. Melo et al., “The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling,” Molecular Psychiatry, vol. 14, no. 8, pp. 764–773, 2009. View at Publisher · View at Google Scholar · View at Scopus
  39. A. M. Magariños and B. S. McEwen, “Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: involvement of glucocorticoid secretion and excitatory amino acid receptors,” Neuroscience, vol. 69, no. 1, pp. 89–98, 1995. View at Publisher · View at Google Scholar · View at Scopus
  40. R. S. Duman and G. K. Aghajanian, “Synaptic dysfunction in depression: potential therapeutic targets,” Science, vol. 338, no. 6103, pp. 68–72, 2012. View at Publisher · View at Google Scholar · View at Scopus
  41. E. Ampuero, F. J. Rubio, R. Falcon et al., “Chronic fluoxetine treatment induces structural plasticity and selective changes in glutamate receptor subunits in the rat cerebral cortex,” Neuroscience, vol. 169, no. 1, pp. 98–108, 2010. View at Publisher · View at Google Scholar · View at Scopus
  42. L. N. Manganas, X. Zhang, Y. Li et al., “Magnetic resonance spectroscopy identifies neural progenitor cells in the live human brain,” Science, vol. 318, no. 5852, pp. 980–985, 2007. View at Publisher · View at Google Scholar · View at Scopus
  43. P. Ramm, S. Couillard-Despres, S. Plötz et al., “A nuclear magnetic resonance biomarker for neural progenitor cells: is it all neurogenesis?” Stem Cells, vol. 27, no. 2, pp. 420–423, 2009. View at Publisher · View at Google Scholar · View at Scopus
  44. M. A. Rueger, H. Backes, M. Walberer et al., “Noninvasive imaging of endogenous neural stem cell mobilization in vivo using positron emission tomography,” Journal of Neuroscience, vol. 30, no. 18, pp. 6454–6460, 2010. View at Publisher · View at Google Scholar · View at Scopus
  45. J. M. Encinas, A. Vaahtokari, and G. Enikolopov, “Fluoxetine targets early progenitor cells in the adult brain,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 21, pp. 8233–8238, 2006. View at Publisher · View at Google Scholar · View at Scopus
  46. E. Segi-Nishida, J. L. Warner-Schmidt, and R. S. Duman, “Electroconvulsive seizure and VEGF increase the proliferation of neural stem-like cells in rat hippocampus,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 32, pp. 11352–11357, 2008. View at Publisher · View at Google Scholar · View at Scopus
  47. T. Weber, V. Baier, K. Lentz et al., “Genetic fate mapping of type-1 stem cell-dependent increase in newborn hippocampal neurons after electroconvulsive seizures,” Hippocampus, vol. 23, no. 12, pp. 1321–1330, 2013. View at Google Scholar
  48. F. Chen, T. M. Madsen, G. Wegener, and J. R. Nyengaard, “Repeated electroconvulsive seizures increase the total number of synapses in adult male rat hippocampus,” European Neuropsychopharmacology, vol. 19, no. 5, pp. 329–338, 2009. View at Publisher · View at Google Scholar · View at Scopus
  49. O. S. Jorgensen, “Synaptic proteins after electroconvulsive stimulation,” Science, vol. 205, no. 4407, pp. 705–707, 1979. View at Google Scholar · View at Scopus
  50. L. Stanton and R. Kohn, “Depression and the aging brain,” Medicine and Health, Rhode Island, vol. 95, no. 7, pp. 210–211, 2012. View at Google Scholar · View at Scopus
  51. A. M. Van Schaik, H. C. Comijs, C. M. Sonnenberg, A. T. Beekman, P. Sienaert, and M. L. Stek, “Efficacy and safety of continuation and maintenance electroconvulsive therapy in depressed elderly patients: a systematic review,” American Journal of Geriatric Psychiatry, vol. 20, no. 1, pp. 5–17, 2012. View at Publisher · View at Google Scholar · View at Scopus
  52. J.-W. Wang, D. J. David, J. E. Monckton, F. Battaglia, and R. Hen, “Chronic fluoxetine stimulates maturation and synaptic plasticity of adult-born hippocampal granule cells,” Journal of Neuroscience, vol. 28, no. 6, pp. 1374–1384, 2008. View at Publisher · View at Google Scholar · View at Scopus
  53. S. Lange, A. Trost, H. Tempfer et al., “Brain pericyte plasticity as a potential drug target in CNS repair,” Drug Discovery Today, vol. 18, no. 9-10, pp. 456–463, 2013. View at Publisher · View at Google Scholar · View at Scopus
  54. J. S. Goldberg and K. K. Hirschi, “Diverse roles of the vasculature within the neural stem cell niche,” Regenerative Medicine, vol. 4, no. 6, pp. 879–897, 2009. View at Publisher · View at Google Scholar · View at Scopus
  55. C. Gemma and A. D. Bachstetter, “The role of microglia in adult hippocampal neurogenesis,” Frontiers in Cellular Neuroscience, vol. 7, article 229, 2013. View at Google Scholar
  56. Q. Shen, S. K. Goderie, L. Jin et al., “Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells,” Science, vol. 304, no. 5675, pp. 1338–1340, 2004. View at Publisher · View at Google Scholar · View at Scopus
  57. H. Song, C. F. Stevens, and F. H. Gage, “Astroglia induce neurogenesis from adult neural stem cells,” Nature, vol. 417, no. 6884, pp. 39–44, 2002. View at Publisher · View at Google Scholar · View at Scopus
  58. A. J. Dwork, V. Arango, M. Underwood et al., “Absence of histological lesions in primate models of ECT and magnetic seizure therapy,” American Journal of Psychiatry, vol. 161, no. 3, pp. 576–578, 2004. View at Publisher · View at Google Scholar · View at Scopus
  59. A. Buffo, I. Rite, P. Tripathi et al., “Origin and progeny of reactive gliosis: a source of multipotent cells in the injured brain,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 9, pp. 3581–3586, 2008. View at Publisher · View at Google Scholar · View at Scopus
  60. C. T. Ekdahl, Z. Kokaia, and O. Lindvall, “Brain inflammation and adult neurogenesis: the dual role of microglia,” Neuroscience, vol. 158, no. 3, pp. 1021–1029, 2009. View at Publisher · View at Google Scholar · View at Scopus
  61. W. J. Streit, “Microglial response to brain injury: a brief synopsis,” Toxicologic Pathology, vol. 28, no. 1, pp. 28–30, 2000. View at Google Scholar · View at Scopus
  62. L. Jansson, M. Wennström, A. Johanson, and A. Tingström, “Glial cell activation in response to electroconvulsive seizures,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 33, no. 7, pp. 1119–1128, 2009. View at Publisher · View at Google Scholar · View at Scopus
  63. A. Schänzer, F.-P. Wachs, D. Wilhelm et al., “Direct stimulation of adult neural stem cells in vitro and neurogenesis in vivo by vascular endothelial growth factor,” Brain Pathology, vol. 14, no. 3, pp. 237–248, 2004. View at Google Scholar · View at Scopus
  64. S. A. Villeda, J. Luo, K. I. Mosher et al., “The ageing systemic milieu negatively regulates neurogenesis and cognitive function,” Nature, vol. 477, no. 7362, pp. 90–96, 2011. View at Publisher · View at Google Scholar · View at Scopus
  65. K. E. Joynt, D. J. Whellan, and C. M. O'Connor, “Depression and cardiovascular disease: mechanisms of interaction,” Biological Psychiatry, vol. 54, no. 3, pp. 248–261, 2003. View at Publisher · View at Google Scholar · View at Scopus
  66. S. Malhotra, G. E. Tesar, and K. Franco, “The relationship between depression and cardiovascular disorders,” Current Psychiatry Reports, vol. 2, no. 3, pp. 241–246, 2000. View at Google Scholar · View at Scopus
  67. H. Takano, N. Motohashi, T. Uema et al., “Changes in regional cerebral blood flow during acute electroconvulsive therapy in patients with depression: positron emission tomographic study,” British Journal of Psychiatry, vol. 190, pp. 63–68, 2007. View at Publisher · View at Google Scholar · View at Scopus
  68. G. Ilbay, C. Dalcik, M. Yardimoglu, H. Dalcik, and E. D. Ubeyli, “The blood-brain barrier and epilepsy,” in Epilepsy—Histological, Electroencephalographic and Psychological Aspects, D. D. Stevanovic, Ed., pp. 31–47, InTech, Rijeka, Croatia, 2012. View at Google Scholar
  69. T. G. Bolwig, M. M. Hertz, and J. Holm-Jensen, “Blood brain barrier permeability during electroshock seizures in the rat,” European Journal of Clinical Investigation, vol. 7, no. 2, pp. 95–100, 1977. View at Google Scholar · View at Scopus
  70. B. Oztas, M. Kaya, and S. Camurcu, “Age related changes in the effect of electroconvulsive shock on the blood brain barrier permeability in rats,” Mechanisms of Ageing and Development, vol. 51, no. 2, pp. 149–155, 1990. View at Publisher · View at Google Scholar · View at Scopus
  71. T. G. Bolwig, M. M. Hertz, and O. B. Paulson, “The permeability of the blood brain barrier during electrically induced seizures in man,” European Journal of Clinical Investigation, vol. 7, no. 2, pp. 87–93, 1977. View at Google Scholar · View at Scopus
  72. A. Sartorius, R. Hellweg, J. Litzke et al., “Correlations and discrepancies between serum and brain tissue levels of neurotrophins after electroconvulsive treatment in rats,” Pharmacopsychiatry, vol. 42, no. 6, pp. 270–276, 2009. View at Publisher · View at Google Scholar · View at Scopus
  73. B. Hattiangady and A. K. Shetty, “Aging does not alter the number or phenotype of putative stem/progenitor cells in the neurogenic region of the hippocampus,” Neurobiology of Aging, vol. 29, no. 1, pp. 129–147, 2008. View at Publisher · View at Google Scholar · View at Scopus
  74. M. Boldrini, R. Hen, M. D. Underwood et al., “Hippocampal angiogenesis and progenitor cell proliferation are increased with antidepressant use in major depression,” Biological Psychiatry, vol. 72, no. 7, pp. 562–571, 2012. View at Publisher · View at Google Scholar · View at Scopus
  75. A. Eichmann and J. L. Thomas, “Molecular parallels between neural and vascular development,” Cold Spring Harbor Perspectives in Medicine, vol. 3, no. 1, Article ID a006551, 2013. View at Google Scholar
  76. J. Hellsten, M. J. West, A. Arvidsson et al., “Electroconvulsive seizures induce angiogenesis in adult rat hippocampus,” Biological Psychiatry, vol. 58, no. 11, pp. 871–878, 2005. View at Publisher · View at Google Scholar · View at Scopus
  77. S. S. Newton, M. J. Girgenti, E. F. Collier, and R. S. Duman, “Electroconvulsive seizure increases adult hippocampal angiogenesis in rats,” European Journal of Neuroscience, vol. 24, no. 3, pp. 819–828, 2006. View at Publisher · View at Google Scholar · View at Scopus
  78. B. S. McEwen, “Stress and hippocampal plasticity,” Annual Review of Neuroscience, vol. 22, pp. 105–122, 1999. View at Publisher · View at Google Scholar · View at Scopus
  79. B. S. McEwen, D. Albeck, H. Cameron et al., “Stress and the brain: a paradoxical role for adrenal steroids,” Vitamins and Hormones, vol. 51, pp. 371–402, 1995. View at Google Scholar
  80. B. A. Samuels and R. Hen, “Neurogenesis and affective disorders,” European Journal of Neuroscience, vol. 33, no. 6, pp. 1152–1159, 2011. View at Publisher · View at Google Scholar · View at Scopus
  81. P. Hu, C. Oomen, A.-M. van Dam et al., “A single-day treatment with mifepristone is sufficient to normalize chronic glucocorticoid induced suppression of hippocampal cell proliferation,” PLoS ONE, vol. 7, no. 9, Article ID e46224, 2012. View at Publisher · View at Google Scholar · View at Scopus
  82. N. R. Nichols, M. Zieba, and N. Bye, “Do glucocorticoids contribute to brain aging?” Brain Research Reviews, vol. 37, no. 1–3, pp. 273–286, 2001. View at Publisher · View at Google Scholar · View at Scopus
  83. C. Mirescu and E. Gould, “Stress and adult neurogenesis,” Hippocampus, vol. 16, no. 3, pp. 233–238, 2006. View at Publisher · View at Google Scholar · View at Scopus
  84. A. Garcia, B. Steiner, G. Kronenberg, A. Bick-Sander, and G. Kempermann, “Age-dependent expression of glucocorticoid- and mineralocorticoid receptors on neural precursor cell populations in the adult murine hippocampus,” Aging Cell, vol. 3, no. 6, pp. 363–371, 2004. View at Publisher · View at Google Scholar · View at Scopus
  85. A. Surget, A. Tanti, E. D. Leonardo et al., “Antidepressants recruit new neurons to improve stress response regulation,” Molecular Psychiatry, vol. 16, no. 12, pp. 1177–1188, 2011. View at Publisher · View at Google Scholar · View at Scopus
  86. P. J. Lucassen, C. P. Fitzsimons, A. Korosi, M. Joels, C. Belzung, and D. N. Abrous, “Stressing new neurons into depression,” Molecular Psychiatry, vol. 18, no. 4, pp. 396–397, 2013. View at Publisher · View at Google Scholar · View at Scopus
  87. S. P. Jung, B. Siegrist, M. R. Wade, C. T. Anthony, and E. A. Woltering, “Inhibition of human angiogenesis with heparin and hydrocortisone,” Angiogenesis, vol. 4, no. 3, pp. 175–186, 2001. View at Publisher · View at Google Scholar · View at Scopus
  88. X. Yang, E. R. Ewald, Y. Huo et al., “Glucocorticoid-induced loss of DNA methylation in non-neuronal cells and potential involvement of DNMT1 in epigenetic regulation of Fkbp5,” Biochemical and Biophysical Research Communications, vol. 420, no. 3, pp. 570–575, 2012. View at Publisher · View at Google Scholar · View at Scopus
  89. J. Hellsten, M. Wennström, P. Mohapel, C. T. Ekdahl, J. Bengzon, and A. Tingström, “Electroconvulsive seizures increase hippocampal neurogenesis after chronic corticosterone treatment,” European Journal of Neuroscience, vol. 16, no. 2, pp. 283–290, 2002. View at Publisher · View at Google Scholar · View at Scopus
  90. J. E. Smith, K. Williams, S. Burkett, H. Nicholson, P. Glue, and D. J. Nutt, “Oxytocin and vasopressin responses to ECT,” Psychiatry Research, vol. 32, no. 2, pp. 201–202, 1990. View at Publisher · View at Google Scholar · View at Scopus
  91. R. Ohman, J. Balldin, and L. Abrahamsson, “Prolactin response to electroconvulsive therapy,” The Lancet, vol. 2, no. 7992, pp. 936–937, 1976. View at Google Scholar · View at Scopus
  92. J. P. Allen, D. Denney, J. W. Kendall, and P. H. Blachly, “Corticotropin release during ECT in man,” American Journal of Psychiatry, vol. 131, no. 11, pp. 1225–1228, 1974. View at Google Scholar · View at Scopus
  93. S. Soelberg, P. Sorensen, M. Hammer, and T. G. Bolwig, “Vasopressin release during electroconvulsive therapy,” Psychoneuroendocrinology, vol. 7, no. 4, pp. 303–308, 1982. View at Publisher · View at Google Scholar · View at Scopus
  94. J. P. Redrobe, Y. Dumont, A. Fournier, and R. Quirion, “The neuropeptide Y (NPY) Y1 receptor subtype mediates NPY-induced antidepressant-like activity in the mouse forced swimming test,” Neuropsychopharmacology, vol. 26, no. 5, pp. 615–624, 2002. View at Publisher · View at Google Scholar · View at Scopus
  95. A. A. Mathé, “Neuropeptides and electroconvulsive treatment,” Journal of ECT, vol. 15, no. 1, pp. 60–75, 1999. View at Google Scholar · View at Scopus
  96. G. Nikisch and A. A. Mathé, “CSF monoamine metabolites and neuropeptides in depressed patients before and after electroconvulsive therapy,” European Psychiatry, vol. 23, no. 5, pp. 356–359, 2008. View at Publisher · View at Google Scholar · View at Scopus
  97. M. Heilig, O. Zachrisson, A. Thorsell et al., “Decreased cerebrospinal fluid neuropeptide Y (NPY) in patients with treatment refractory unipolar major depression: preliminary evidence for association with preproNPY gene polymorphism,” Journal of Psychiatric Research, vol. 38, no. 2, pp. 113–121, 2004. View at Publisher · View at Google Scholar · View at Scopus
  98. M. Nibuya, S. Morinobu, and R. S. Duman, “Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments,” Journal of Neuroscience, vol. 15, no. 11, pp. 7539–7547, 1995. View at Google Scholar · View at Scopus
  99. S. S. Newton, E. F. Collier, J. Hunsberger et al., “Gene profile of electroconvulsive seizures: induction of neurotrophic and angiogenic factors,” Journal of Neuroscience, vol. 23, no. 34, pp. 10841–10851, 2003. View at Google Scholar · View at Scopus
  100. C. A. Altar, P. Laeng, L. W. Jurata et al., “Electroconvulsive seizures regulate gene expression of distinct neurotrophic signaling pathways,” Journal of Neuroscience, vol. 24, no. 11, pp. 2667–2677, 2004. View at Publisher · View at Google Scholar · View at Scopus
  101. J. Hellsten, M. Wennström, J. Bengzon, P. Mohapel, and A. Tingström, “Electroconvulsive seizures induce endothelial cell proliferation in adult rat hippocampus,” Biological Psychiatry, vol. 55, no. 4, pp. 420–427, 2004. View at Publisher · View at Google Scholar · View at Scopus
  102. M. Wennström, J. Hellsten, and A. Tingström, “Electroconvulsive seizures induce proliferation of NG2-expressing glial cells in adult rat amygdala,” Biological Psychiatry, vol. 55, no. 5, pp. 464–471, 2004. View at Publisher · View at Google Scholar · View at Scopus
  103. G. S. Naeve, M. Ramakrishnan, R. Kramer, D. Hevroni, Y. Citri, and L. E. Theill, “Neuritin: a gene induced by neural activity and neurotrophins that promotes neuritogenesis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 6, pp. 2648–2653, 1997. View at Google Scholar
  104. D. J. Bonthius, B. Karacay, D. Dai, and N. J. Pantazis, “FGF-2, NGF and IGF-1, but not BDNF, utilize a nitric oxide pathway to signal neurotrophic and neuroprotective effects against alcohol toxicity in cerebellar granule cell cultures,” Developmental Brain Research, vol. 140, no. 1, pp. 15–28, 2003. View at Publisher · View at Google Scholar · View at Scopus
  105. J. L. Warner-Schmidt and R. S. Duman, “VEGF is an essential mediator of the neurogenic and behavioral actions of antidepressants,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 11, pp. 4647–4652, 2007. View at Publisher · View at Google Scholar · View at Scopus
  106. K. Jin, Y. Zhu, Y. Sun, X. O. Mao, L. Xie, and D. A. Greenberg, “Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 18, pp. 11946–11950, 2002. View at Publisher · View at Google Scholar · View at Scopus
  107. T. G. Bolwig, “How does electroconvulsive therapy work? Theories on its mechanism,” Canadian Journal of Psychiatry, vol. 56, no. 1, pp. 13–18, 2011. View at Google Scholar · View at Scopus
  108. Y. Shirayama, A. C.-H. Chen, S. Nakagawa, D. S. Russell, and R. S. Duman, “Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression,” Journal of Neuroscience, vol. 22, no. 8, pp. 3251–3261, 2002. View at Google Scholar · View at Scopus
  109. J. A. Siuciak, D. R. Lewis, S. J. Wiegand, and R. M. Lindsay, “Antidepressant-like effect of brain-derived neurotrophic factor (BDNF),” Pharmacology, Biochemistry, and Behavior, vol. 56, no. 1, pp. 131–137, 1997. View at Google Scholar
  110. E. Segi-Nishida, “Exploration of new molecular mechanisms for antidepressant actions of electroconvulsive seizure,” Biological and Pharmaceutical Bulletin, vol. 34, no. 7, pp. 939–944, 2011. View at Publisher · View at Google Scholar · View at Scopus
  111. M. Sairanen, G. Lucas, P. Ernfors, M. Castrén, and E. Castrén, “Brain-derived neurotrophic factor and antidepressant drugs have different but coordinated effects on neuronal turnover, proliferation, and survival in the adult dentate gyrus,” Journal of Neuroscience, vol. 25, no. 5, pp. 1089–1094, 2005. View at Publisher · View at Google Scholar · View at Scopus
  112. T. Saarelainen, P. Hendolin, G. Lucas et al., “Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects,” Journal of Neuroscience, vol. 23, no. 1, pp. 349–357, 2003. View at Google Scholar · View at Scopus
  113. O. Kampman and E. Leinonen, “Efficacy of electroconvulsive therapy: is it in the BDNF gene?” Pharmacogenomics, vol. 14, no. 12, pp. 1365–1368, 2013. View at Google Scholar
  114. P. Pruunsild, A. Kazantseval, T. Aid, K. Palm, and T. Timmusk, “Dissecting the human BDNF locus: bidirectional transcription, complex splicing, and multiple promoters,” Genomics, vol. 90, no. 3, pp. 397–406, 2007. View at Publisher · View at Google Scholar · View at Scopus
  115. D. Suri, V. Veenit, A. Sarkar et al., “Early stress evokes age-dependent biphasic changes in hippocampal neurogenesis, Bdnf expression, and cognition,” Biological Psychiatry, vol. 73, no. 7, pp. 658–666, 2013. View at Publisher · View at Google Scholar · View at Scopus
  116. H. Kaija, A. Sami, H. Martti et al., “Brain-derived neurotrophic factor (BDNF) polymorphisms G196A and C270T are not associated with response to electroconvulsive therapy in major depressive disorder,” European Archives of Psychiatry and Clinical Neuroscience, vol. 257, no. 1, pp. 31–35, 2007. View at Publisher · View at Google Scholar · View at Scopus
  117. S. Campbell, M. Marriott, C. Nahmias, and G. M. MacQueen, “Lower hippocampal volume in patients suffering from depression: a meta-analysis,” American Journal of Psychiatry, vol. 161, no. 4, pp. 598–607, 2004. View at Publisher · View at Google Scholar · View at Scopus
  118. R. S. Duman, G. R. Heninger, and E. J. Nestler, “A molecular and cellular theory of depression,” Archives of General Psychiatry, vol. 54, no. 7, pp. 597–606, 1997. View at Google Scholar
  119. E. J. Nestler, M. Barrot, R. J. DiLeone, A. J. Eisch, S. J. Gold, and L. M. Monteggia, “Neurobiology of depression,” Neuron, vol. 34, no. 1, pp. 13–25, 2002. View at Publisher · View at Google Scholar · View at Scopus
  120. Y. I. Sheline, M. H. Gado, and H. C. Kraemer, “Untreated depression and hippocampal volume loss,” American Journal of Psychiatry, vol. 160, no. 8, pp. 1516–1518, 2003. View at Publisher · View at Google Scholar · View at Scopus
  121. P. Videbech and B. Ravnkilde, “Hippocampal volume and depression: a meta-analysis of MRI studies,” American Journal of Psychiatry, vol. 161, no. 11, pp. 1957–1966, 2004. View at Publisher · View at Google Scholar · View at Scopus
  122. D. Cotter, D. Mackay, S. Landau, R. Kerwin, and I. Everall, “Reduced glial cell density and neuronal size in the anterior cingulate cortex in major depressive disorder,” Archives of General Psychiatry, vol. 58, no. 6, pp. 545–553, 2001. View at Google Scholar · View at Scopus
  123. G. Rajkowska, J. J. Miguel-Hidalgo, J. Wei et al., “Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression,” Biological Psychiatry, vol. 45, no. 9, pp. 1085–1098, 1999. View at Publisher · View at Google Scholar · View at Scopus
  124. D. Öngür, W. C. Drevets, and J. L. Price, “Glial reduction in the subgenual prefrontal cortex in mood disorders,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 22, pp. 13290–13295, 1998. View at Publisher · View at Google Scholar · View at Scopus
  125. I. Tendolkar, M. van Beek, I. van Oostrom et al., “Electroconvulsive therapy increases hippocampal and amygdala volume in therapy refractory depression: a longitudinal pilot study,” Psychiatry Research, vol. 214, no. 3, pp. 197–203, 2013. View at Google Scholar
  126. M. G. Cole, F. Bellavance, and A. Mansour, “Prognosis of depression in elderly community and primary care populations: a systematic review and meta-analysis,” American Journal of Psychiatry, vol. 156, no. 8, pp. 1182–1189, 1999. View at Google Scholar · View at Scopus
  127. J. M. Parent and G. G. Murphy, “Mechanisms and functional significance of aberrant seizure-induced hippocampal neurogenesis,” Epilepsia, vol. 49, supplement 5, pp. 19–25, 2008. View at Publisher · View at Google Scholar · View at Scopus
  128. S. R. Lamont, A. Paulls, and C. A. Stewart, “Repeated electroconvulsive stimulation, but not antidepressant drugs, induces mossy fibre sprouting in the rat hippocampus,” Brain Research, vol. 893, no. 1-2, pp. 53–58, 2001. View at Publisher · View at Google Scholar · View at Scopus
  129. V. A. Vaidya, J. A. Siuciak, F. Du, and R. S. Duman, “Hippocampal mossy fiber sprouting induced by chronic electroconvulsive seizures,” Neuroscience, vol. 89, no. 1, pp. 157–166, 1999. View at Publisher · View at Google Scholar · View at Scopus
  130. J. M. Parent and D. H. Lowenstein, “Seizure-induced neurogenesis: are more new neurons good for an adult brain?” Progress in Brain Research, vol. 135, pp. 121–131, 2002. View at Publisher · View at Google Scholar · View at Scopus
  131. C. Schmidt-Hieber, P. Jones, and J. Bischofberger, “Enhanced synaptic plasticity in newly generated granule cells of the adult hippocampus,” Nature, vol. 429, no. 6988, pp. 184–187, 2004. View at Publisher · View at Google Scholar · View at Scopus
  132. S. Ge, C.-H. Yang, K.-S. Hsu, G.-L. Ming, and H. Song, “A critical period for enhanced synaptic plasticity in newly generated neurons of the adult brain,” Neuron, vol. 54, no. 4, pp. 559–566, 2007. View at Publisher · View at Google Scholar · View at Scopus
  133. S. Couillard-Despres, B. Winner, S. Schaubeck et al., “Doublecortin expression levels in adult brain reflect neurogenesis,” European Journal of Neuroscience, vol. 21, no. 1, pp. 1–14, 2005. View at Publisher · View at Google Scholar · View at Scopus
  134. V. M. Heine, J. Zareno, S. Maslam, M. Joëls, and P. J. Lucassen, “Chronic stress in the adult dentate gyrus reduces cell proliferation near the vasculature and VEGF and Flk-1 protein expression,” European Journal of Neuroscience, vol. 21, no. 5, pp. 1304–1314, 2005. View at Publisher · View at Google Scholar · View at Scopus
  135. A. H. Nagahara, M. Mateling, I. Kovacs et al., “Early BDNF treatment ameliorates cell loss in the entorhinal cortex of APP transgenic mice,” The Journal of Neuroscience, vol. 33, no. 39, pp. 15596–15602, 2013. View at Google Scholar