Neural Plasticity / 2011 / Article / Fig 1

Review Article

GABA Neuron Alterations, Cortical Circuit Dysfunction and Cognitive Deficits in Schizophrenia

Figure 1

Scheme showing a nerve terminal from a parvalbumin- (PV-) positive GABA neuron shortly after an action potential triggered Ca2+-dependent GABA release, highlighting components currently hypothesized to be altered in schizophrenia. In PV terminals, GABA release is tightly synchronized with Ca2+ influx, possibly due to the proximity between voltage-dependent Ca2+ channels and release sites. PV is a relatively slow buffer that probably is unable to bind Ca2+ before activation of the Ca2+ sensor promotes vesicle fusion. Ca2+ buffering by PV mainly accelerates the decay of the intraterminal Ca2+ transient (see text). GAD65 and GAD67, possibly acting as a dimer, drive GABA synthesis in the cytosol near synaptic vesicles. Vesicles uptake newly synthesized GABA via the vesicular GABA transporter vGAT. Vesicle fusion rapidly and transiently raises GABA concentration in the synaptic cleft, briefly exposing post-synaptic GABAA receptors (GABAARs) to a high concentration of GABA. As GABA escapes from the synaptic cleft after GABAAR activation, it may be taken up by the plasma membrane GABA transporter GAT1, apparently localized in the extrasynaptic neuronal membrane, as well as in glia. GAT1 therefore regulates the concentration of GABA reaching extrasynaptic GABAARs and synaptic GABAARs at other synapses (not shown in the scheme). The direction and magnitude of the chloride current produced by postsynaptic GABAAR activation is regulated by the transporters KCC2 and NKCC1, which uptake and extrude chloride, respectively, setting the equilibrium potential for the GABAA current, 𝐸 G A B A A . Since PV accelerates the decay of the intraterminal Ca2+ transients, a decrease of PV in schizophrenia may facilitate repetitive GABA release, such as that observed during gamma oscillation episodes. A decrease of GAD67 levels in schizophrenia would reduce the cytosolic GABA concentration near synaptic vesicles. Because vGAT levels appear to be unaffected in schizophrenia, reduced GAD67 may lead to lower intravesicular GABA concentration, therefore decreasing the peak GABA concentration in the synaptic cleft and weakening the postsynaptic response. In schizophrenia, at some synapses postsynaptic GABAAR density appears to be decreased, further weakening synaptic transmission, whereas at other synapses GABAAR density is increased, possibly due to compensatory receptor upregulation. In schizophrenia, KCC2 and NKCC1 mRNA levels are normal, but two kinases that strongly regulate KCC2 and NKCC1 may be altered in ways that render an 𝐸 G A B A A value more depolarizing than normal. Finally, reduced GAT1 in schizophrenia may alter the effects of synaptically released GABA via an exaggerated activation of extrasynaptic and heterosynaptic GABAARs. Alternatively, GAT1 activity may be reduced to compensate lower GABA levels due to GAD67 deficiency.

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