In individuals with schizophrenia the expression level of PV mRNA is reduced, although the number of PV A-1210477 molecular weight neurons appears to be unchanged56; in addition, approximately half of PV mRNA-containing neurons lack detectable levels of GAD67 mRNA.57 In contrast, the -50% of GABA neurons that express the calcium binding protein calretinin appear to be unaffected.57 Figure 3 Schematic summary of putative alterations in DLPFC circuitry in schizophrenia. Pyramidal neurons (light blue) in deep layer 3 have smaller

somal size, shorter basilar dendrites, lower dendritic spine Inhibitors,research,lifescience,medical density, and a reduced axonal arbor in schizophrenia. Inhibitors,research,lifescience,medical … In the DLPFC of subjects with schizophrenia, G ATI immunore activity is selectively reduced in the characteristic axon terminals (cartridges) of PV-containing chandelier neurons.58 In the postsynaptic

targets of these axon cartridges, the axon initial segments of pyramidal neurons, immunoreactivity for the GABAA receptor α2 subunit (which is present in most GABAA receptors in this location59) is markedly increased in schizophrenia.60 Several lines of evidence suggest that the reductions in presynaptic GABA markers (GAT1 and PV) and increased Inhibitors,research,lifescience,medical postsynaptic GABAA receptors are compensatory responses Inhibitors,research,lifescience,medical to a deficit in GABA release from chandelier neurons. For example, PV is a slow calcium buffer that does not affect the amplitude, but accelerates the decay, of Ca2+ transients in GABA nerve terminals.61,62 Thus, PV decreases the residual Ca2+ levels that normally accumulate in nerve terminals and facilitate GABA release during repetitive firing.61 Studies Inhibitors,research,lifescience,medical in PV-deficient mice have demonstrated that a decrease in PV increases residual Ca2+ and

favors synaptic facilitation.61,63 Furthermore, the enhanced facilitation of GABA release from fast-spiking neurons with reductions in PV is associated with increased power of gamma oscillations63 (which is, as explained below, deficient in schizophrenia). Similarly, the blockade of Liothyronine Sodium GABA reuptake via GAT1 prolongs the duration of inhibitory postsynaptic currents (IPSCs) when synapses located close to each other are activated synchronously64; the resulting prolongation of IPSCs increases the probability of IPSC summation, enhances the total efficacy of IPSC trains, and thereby augments GABA signaling. The upregulation of the postsynaptic GABAA receptors that contain α2, subunits would be expected to increase the efficacy of the GABA that is released from chandelier neurons.