Altered Inhibitory Prefrontal Circuitry in Schizophrenia

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DESCRIPTION :(provided by the applicant) Disturbances in GABA neurons, particularly chandelier cells, appear to play a prominent role in the dysfunction of prefrontal cortical (PFC) circuitry in schizophrenia. However, it is unclear whether alterations in chandelier neurons result in decreased inhibitory input to their postsynaptic targets, the axon initial segments (AIS) of pyramidal neurons. Furthermore, the mechanisms that initiate disturbances in PPC GABA neurons are unknown. Interestingly, several studies report abnormalities in the mediodorsal thalamic nucleus ( about)TN), a major source of excitatory input to the PFC. However, it is unknown whether reduced MDTN input produces alterations in PFC GABA neurons similar to those observed in schizophrenia. Consequently, in Study 1, we will determine whether presynaptic alterations in chandelier neuron axon terminals are associated with postsynaptic changes in GABA receptor irnmunoreactivity in pyrarnidal neuron AIS in the PFC in schizophrenia. In PFC area 46 from matched pairs of schizophrenic and control subjects, the relative density of AIS immunoreactive for the alpha-2,3 subunits will be determined using systematic, random sampling. We will also deterrnine whether any changes are unique to the diagnosis of schizophrenia, or related to antipsychotic treatment, by studying subjects with major depression, some of whom were treated for psychosis. In Study 2, we will determine whether cellular lesions of the MDTN result in changes in GABA markers in the PFC of nonhuman primates, in whom the anatomical characteristics of the MDTN and PFC are similar to humans. After a 3 month survival period, we will quantify any changes in the mRNA expression of PFC GABA markers using in situ hybridization and grain counting techniques.