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

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37MH043784-21
Application #
7760106
Study Section
Special Emphasis Panel (NSS)
Program Officer
Meinecke, Douglas L
Project Start
1988-09-30
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2012-01-31
Support Year
21
Fiscal Year
2010
Total Cost
$750,749
Indirect Cost
Name
University of Pittsburgh
Department
Psychiatry
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Arion, Dominique; Huo, Zhiguang; Enwright, John F et al. (2017) Transcriptome Alterations in Prefrontal Pyramidal Cells Distinguish Schizophrenia From Bipolar and Major Depressive Disorders. Biol Psychiatry 82:594-600
Datta, Dibyadeep; Arion, Dominique; Roman, Kaitlyn M et al. (2017) Altered Expression of ARP2/3 Complex Signaling Pathway Genes in Prefrontal Layer 3 Pyramidal Cells in Schizophrenia. Am J Psychiatry 174:163-171
Glausier, Jill R; Lewis, David A (2017) GABA and schizophrenia: Where we stand and where we need to go. Schizophr Res 181:2-3
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Rocco, Brad R; Lewis, David A; Fish, Kenneth N (2016) Markedly Lower Glutamic Acid Decarboxylase 67 Protein Levels in a Subset of Boutons in Schizophrenia. Biol Psychiatry 79:1006-15
Lewis, David A; Glausier, Jill R (2016) Alterations in Prefrontal Cortical Circuitry and Cognitive Dysfunction in Schizophrenia. Nebr Symp Motiv 63:31-75
Chung, Daniel W; Fish, Kenneth N; Lewis, David A (2016) Pathological Basis for Deficient Excitatory Drive to Cortical Parvalbumin Interneurons in Schizophrenia. Am J Psychiatry 173:1131-1139
Chung, Daniel W; Volk, David W; Arion, Dominique et al. (2016) Dysregulated ErbB4 Splicing in Schizophrenia: Selective Effects on Parvalbumin Expression. Am J Psychiatry 173:60-8
Enwright, John F; Sanapala, Sowmya; Foglio, Aaron et al. (2016) Reduced Labeling of Parvalbumin Neurons and Perineuronal Nets in the Dorsolateral Prefrontal Cortex of Subjects with Schizophrenia. Neuropsychopharmacology 41:2206-14
Volk, D W; Sampson, A R; Zhang, Y et al. (2016) Cortical GABA markers identify a molecular subtype of psychotic and bipolar disorders. Psychol Med 46:2501-12

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