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

Figure 3

Diversity of perisomatic-targeting GABA neuron-mediated inhibition in cortical circuits may be due to differences in the reversal potential for the GABA_A-mediated current. (a) The scheme illustrates targeting by basket cells (either parvalbumin- or cholechystokinin-positive), which contact the soma and the proximal/perisomatic dendritic compartments, and by chandelier or axoaxonic neurons, which contact the axon initial segment. (b) The schemes illustrate differences in the postsynaptic effect of a GABA_AR conductance according to the value of the reversal potential for the GABA_A current (𝐸_GABAA) relative to the resting membrane potential (𝑉_mr) and the threshold potential to fire spikes (𝑉_th). In (B1) to (B3), the time course of the GABA_AR-mediated conductance, chosen to be identical in all panels, is shown by the black traces and the IPSPs are shown by the blue/red traces. Note that the IPSP time course is always slower than the GABA_A conductance, although in the scheme the difference in time course is somewhat exaggerated for illustration purposes and does not match the actual time scales. (B1) Illustration of cases in which 𝐸_GABAA is negative relative to 𝑉_mr(𝑉_th>𝑉_mr>𝐸_GABAA), and the GABA_A conductance generates a hyperpolarizing IPSP (all blue IPSP trace). As the IPSP outlasts the GABA_A conductance, the duration of the inhibitory effect of the synaptic input (shown by the shaded blue rectangle) is extended by the membrane hyperpolarization that remains after the GABA_A conductance decays. (B2) Illustration of cases in which the IPSP is depolarizing because 𝐸_GABAA is positive relative to 𝑉_mr(𝑉_th>𝐸_GABAA>𝑉_mr). Just as the hyperpolarizing IPSP, the depolarizing IPSP outlasts the GABA_A conductance; however, in this case 𝐸_GABAA is below 𝑉_th, and therefore the depolarizing IPSP could have a dual inhibitory/excitatory effect (blue/red IPSP trace), initially producing shunting inhibition which lasts approximately the same time as the GABA_A conductance (shaded blue/red rectangle), followed by an enhanced excitability of the postsynaptic neuron due to the remaining phase of the depolarizing IPSP. (B3) Illustration of cases in which 𝐸_GABAA is positive relative to 𝑉_th(𝐸_GABAA>𝑉_th>𝑉_mr). In this case, the depolarizing IPSP has a purely excitatory effect (shaded red rectangle). Basket cells are thought to produce hyperpolarizing GABA_AR-mediated inhibition of pyramidal cells such as that illustrated in (B1). In contrast, the effect of chandelier neuron inputs is currently debatable, some studies suggesting an excitatory as that in (B3), other studies suggesting a purely inhibitory effect. Here, we suggest that depolarizing chandelier cell inputs may have a dual inhibitory/excitatory effect, illustrated in (B2), which could synchronize postsynaptic cells as described in Figure 2, although the depolarizing nature of the IPSP may accelerate the timing of synchronous firing after the postsynaptic cells escape from inhibition.

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