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 GABA_A receptors (GABA_ARs) to a high concentration of GABA. As GABA escapes from the synaptic cleft after GABA_AR 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 GABA_ARs and synaptic GABA_ARs at other synapses (not shown in the scheme). The direction and magnitude of the chloride current produced by postsynaptic GABA_AR activation is regulated by the transporters KCC2 and NKCC1, which uptake and extrude chloride, respectively, setting the equilibrium potential for the GABA_A current, 𝐸_GABAA. 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 GABA_AR density appears to be decreased, further weakening synaptic transmission, whereas at other synapses GABA_AR 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_GABAA 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 GABA_ARs. Alternatively, GAT1 activity may be reduced to compensate lower GABA levels due to GAD67 deficiency.