GABA Neurons and Cortical Circuitry in Schizophrenia

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

Investigators

Linked publications & trials

Abstract

DESCRIPTION: (provided by applicant) Some of the cognitive symptoms of[unreadable] schizophrenia have been attributed to dysfunction of the dorsal prefrontal[unreadable] cortex (dPFC), and this dysfunction appears to be associated with alterations[unreadable] of the neural circuitry within the dPFC and in its connections with the[unreadable] mediodorsal nucleus (MDN) of the thalamus. In the dPFC, these alterations[unreadable] include disturbances in markers of GABA neurotransmission that are restricted[unreadable] to a subset of GABA neurons. The studies proposed in this application are[unreadable] designed to identify the affected subset of GABA neurons, to define the[unreadable] postsynaptic consequences of the alterations in these neurons, and to[unreadable] characterize the pathophysiological mechanisms that may produce these[unreadable] alterations. Specifically, we plan to test the following hypotheses: 1) The[unreadable] affected subset of dPFC GABA neurons in schizophrenia is composed principally[unreadable] of the chandelier and wide arbor subclasses, which are specialized for potent[unreadable] inhibitory control over cortical pyramidal neuron activity. 2) The disturbances[unreadable] in these GABA neurons are accompanied by changes in the GABA-A receptor subunit[unreadable] proteins that are postsynaptic to the axon terminals of chandelier and wide[unreadable] arbor neurons. 3) In the dPFC of subjects with schizophrenia, the expression[unreadable] pattern of genes involved in GABA neurotransmission is consistent with[unreadable] alterations in chandelier and wide arbor neuron connectivity. 4) These changes[unreadable] in pre- and postsynaptic markers of GABA neurotransmission are specific to the[unreadable] pathophysiology of schizophrenia. 5) Altered GABA markers are not restricted to[unreadable] the dPFC in schizophrenia, but are also found in other cortical regions that[unreadable] receive input from the MDN. 6) Experimental lesions of MDN neurons in macaque[unreadable] monkeys produce changes in dPFC GABA neurons similar to those seen in[unreadable] schizophrenia. The power of the proposed studies derives from an integration of[unreadable] molecular and anatomical approaches, in both humans and nonhuman primates to[unreadable] test hypotheses regarding the circuit-specificity and underlying causes of[unreadable] altered dPFC GABA neurotransmission in schizophrenia. Together, these studies[unreadable] will provide a comprehensive molecular-and circuit-based accounting of the[unreadable] contribution of abnormalities in GABA neurotransmission to dPFC dysfunction in[unreadable] schizophrenia.