Copyright © 2008 C. Andrew Chapman 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.
The entorhinal cortex (EC) is a unique and fascinating structure, constituting a highly
parallel interface between phylogenetically old cortex (hippocampus) and higher
neocortical areas. The literature related to the EC has increased dramatically
in the past 30 years. A simple PubMed search for EC lists around 20–40 articles per
year in the early 1980s. This more than doubled by the beginning of the 1990s
and doubled again by the start of the new century. Throughout the current
decade, some 220–250 papers per
year relating to structure, function, and pathology of the EC have been
published, and the numbers are still rising. It has become increasingly
apparent that the EC can no longer be regarded as a simple relay between the
hippocampus and neocortex, but is a dynamic processor of both efferent and
afferent information. In recent years,
there has been burgeoning interest in synaptic plasticity at entorhinal
synapses particularly in relationship
with learning and memory functions of limbic structures. Neuroplasticity
in the EC clearly takes many forms. In
addition to the “input” and “output” roles that have long been ascribed to the
superficial and deep layers, functions of the entorhinal area have been studied
with respect to differences in the medial and lateral divisions, prominent
state-dependent theta- and gamma-frequency population activities, membrane
conductances that shape cellular and network activities, the neurophysiology of
synaptic inputs from other regions and interlaminar connections, and the
powerful roles of modulatory transmitter systems and local inhibition. The
discovery of grid cells in the EC has led to strong interest in the role of the
area in spatial processing. On the other
side of the coin, long-term adaptive changes in EC function also appear to play
pivotal roles in neuropathological states, particularly epilepsy, schizophrenia,
and Alzheimer’s disease.
Contributions to this special issue of Neural Plasticity provide an overview
of some of the theoretical and methodological approaches that are being applied
to understand the functions and mechanisms of neuroplasticity within the
EC. The research contained in this
special issue deals mainly with findings derived from animal research. It is clear, however, that research using a variety
of techniques is providing insight into entorhinal function in human and
clinical populations.
The significance
of plasticity in the EC is best understood within the context provided by
anatomical knowledge of the extrinsic and intrinsic connectivity of this area. Canto et al. have provided an excellent
overview of the anatomical organization of the EC. Their analysis of intrinsic and extrinsic
connections, in relationship to laminar organization and neuronal subtypes,
heavily underscores our increasing perception of the EC as a dynamic
interactive processor essential to hippocampal function, rather than a passive
route of information entry and exit. The
EC is tightly intertwined with circuitries of the hippocampal formation and
other cortical areas, and its particular contributions to sensory processing,
learning, memory, and motor behavior have been difficult to define. Lipton and Eichenbaum present evidence dealing with the complementary roles of the EC and
hippocampus in episodic memory. They have
found that medial EC neurons show
stronger trajectory-dependent firing whereas hippocampal place cells show
greater spatial specificity. Based on these observations, they propose roles of
the hippocampus and medial EC in encoding sequences of events and
disambiguating overlapping experiences, respectively. A contribution by
Bevilaqua et al. also highlights the role of the EC in extinction learning and
how this is affected by ageing. They
raise the possibility that ageing-associated impairment of extinction may occur
in part because of degenerative changes in the EC.
Several articles
in the special issue have investigated mechanisms of long-term,
activity-dependent synaptic plasticity. Ma et al. observed
differences in the induction of long-term synaptic potentiation (LTP) in the
superficial neurones of the EC; LTP in horizontal (potentially extrinsic) inputs required NMDA
receptor activation whereas LTP in interlaminar (intrinsic) inputs did not.
This underlines the potential complexity of information processing in neurones
that provides the bulk of hippocampal afferent inputs. Hernández et al. have found that prenatal
malnutrition has lasting effects on the capacity of the EC to express LTP, and
it is possible that this reduced plasticity may contribute to deficits in
learning and memory in the adult. In
addition to LTP, there is a growing body of literature dealing with
characteristics of long-term depression (LTD) in the EC. Kourrich et al. have investigated the
postsynaptic signaling mechanisms that mediate entorhinal LTD, and provide
further evidence for the roles of calcium-dependent signaling and protein
phosphatases in the expression of LTD in the superficial layers. Much of the interest in long-term changes in
synaptic strength has traditionally been driven by interest in mnemonic
processes and neurological disorders. Short-term activity-dependent changes in synaptic strength also have
powerful influences on ongoing synaptic transmission in the EC. In this issue, Chamberlain et al. have continued their work on
the role of presynaptic NMDA autoreceptors in excitatory transmission in layer
V of the EC. They demonstrate that presynaptic NR2B subunits are critical in
enhancement of both spontaneous glutamate release and frequency-dependent facilitation
of action potential-driven release. The kinetics of these receptors provide an
optimal facilitation frequency of 3–6 Hz, and the
authors speculate on the possible involvement of the autoreceptors in
generation of delta/theta oscillations in mnemonic processing and
epileptogenesis.
The EC is subject
to the powerful influence of several neuromodulatory transmitters including
acetylcholine, serotonin, and dopamine. One of the articles in the special
issue, from Caruana and Chapman, describes the dose-dependent, bidirectional
effect of dopamine on the amplitude of evoked synaptic responses in layer II of
the lateral EC. The significance of this
bidirectional effect for entorhinal function is as yet unclear, but there are
interesting parallels with bidirectional effects of dopamine in prefrontal
cortex.
Oscillatory
neuronal population activities are known to contribute to the synchronization
of neuronal activity in cortical areas throughout the brain, and the mechanisms
that generate theta- and gamma-frequency activities in the EC are being
examined. Kainic acid induces powerful
gamma oscillations in layer III of the EC, and Stanger et al. demonstrate here
that the GL subunit is required for kainate-induced gamma
activity in the EC. Morgan et al. also
examined kainate-induce oscillations in the beta/gamma range in EC with respect
to the action of cannabinoid receptors. Their experiments suggest that CB1 receptors are constitutively
active in the EC and that antagonists or inverse agonists enhanced beta/gamma
oscillations in layer II but suppressed oscillations in layer V, again pointing
to differential control of synchrony in neurons providing afferent input to the
hippocampus and those receiving output from it. Hasselmo and Brandon have
examined how oscillations in membrane potential in entorhinal neurons, combined
with the unique persistent firing activity in these cells, may contribute to
several phenomena. This provides an
excellent example of how quantitative analysis of cellular and network properties
of the EC can lead to a greater understanding of mechanisms of cognition and
behavior. The role of oscillatory
activity in regulating large-scale interactions between the hippocampal
formation and the neocortex has come under increased study in the past several
years as several labs have begun to examine concurrent changes in oscillatory
EEG activity in hippocampus and neocortex associated with sleep and waking states. In the current issue, Axmacher et al. describe results obtained from scalp and intracranial EEG recordings from epilepsy patients that show increased correlations between oscillations in the neocortex and medial temporal lobe including the rhinal cortex during non-REM sleep; the increased correlation may support mechanisms related to memory consolidation.
Our hope is that this special issue of Neural Plasticity will serve to
emphasize the diversity of phenomena related to neural plasticity in the EC,
and to highlight the importance of these effects, particularly in relationship
to the increasing perception of the participation of the EC in mnemonic
function of temporal lobe memory circuits and its related roles in integration
of spatial information.
C. Andrew Chapman
Roland S. G. Jones
Min Jung