Morphological and molecular alterations in the circuitry of the dorsolateral prefrontal cortex (PFC) appear to contribute to the cognitive deficits in schizophrenia. In layer 3, these alterations include ~20% fewer dendritic spines, the principal site of excitatory inputs to pyramidal (PYR) neurons, and lower expression of glutamic acid decarboxylase 67 (GAD67), the enzyme responsible for most GABA synthesis, in parvalbumin (PV)- containing interneurons. Thus, schizophrenia appears to be associated lower levels of both excitation and inhibition in PFC layer 3. In monkey PFC, layer 3 PYR and PV neurons form a local network. PYR-to-PYR cell connections mediate recurrent excitation in the network and the PV-to-PYR cell connections mediate feedback inhibition. The proper weighting of activity in these connections maintains the balance between excitation and inhibition (E/I balance) that allows activity to propagate through the network without either dying out or increasing uncontrollably. E/I balance is maintained in the face of prolonged perturbations in circuit activity by adjustments in the levels of excitatory and inhibitory synaptic transmission through a process termed synaptic scaling or homeostatic synaptic plasticity (HSP). We propose (hypothesis H1) that the proximal or """"""""upstream"""""""" cortical pathology in schizophrenia is a deficit in dendritic spines (and a corresponding loss of excitatory inputs) that is intrinsic to layer 3 PYR neurons. The resulting decrease in network activity evokes HSP signaling mechanisms that persistently increase mediators of local recurrent excitatory inputs and decrease mediators of PV cell feedback inhibition to layer 3 PYR neurons. Alternatively, lower expression of GAD67 in PV cells and reduced network inhibition could be the proximal pathology leading to the opposite pattern of synaptic changes (hypothesis H2). These hypotheses are tested in postmortem studies of schizophrenia (Aims 1 &2), and in proof-of-concept studies in mice with experimental reductions in either PYR cell dendritic spines or GAD67 expression in PV cells (Aim 3). The findings from this """"""""cause-compensation"""""""" analysis of PFC circuitry will provide insight into potential targets for new therapeutic interventions in schizophrenia, and how each target should be manipulated. Thus, the proposed studies directly address NIMH Strategic Plan initiatives to use an understanding of neural circuitry and plasticity to develop novel therapies.

Public Health Relevance

Through the use of innovative techniques and an explanatory model from basic neuroscience, the proposed studies provide a powerful strategy for distinguishing between cause and compensation in cortical circuitry alterations in schizophrenia. This distinction is essential for identifying pathophysiologically-based targets for novel therapeutic interventions that either ameliorate the cause or enhance the compensation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH043784-22
Application #
8107153
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Meinecke, Douglas L
Project Start
1988-09-30
Project End
2016-04-30
Budget Start
2011-07-25
Budget End
2012-04-30
Support Year
22
Fiscal Year
2011
Total Cost
$712,228
Indirect Cost
Name
University of Pittsburgh
Department
Psychiatry
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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
Glausier, Jill R; Roberts, Rosalinda C; Lewis, David A (2017) Ultrastructural analysis of parvalbumin synapses in human dorsolateral prefrontal cortex. J Comp Neurol 525:2075-2089
Chung, Daniel W; Wills, Zachary P; Fish, Kenneth N et al. (2017) Developmental pruning of excitatory synaptic inputs to parvalbumin interneurons in monkey prefrontal cortex. Proc Natl Acad Sci U S A 114:E629-E637
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
Enwright Iii, J F; Huo, Z; Arion, D et al. (2017) Transcriptome alterations of prefrontal cortical parvalbumin neurons in schizophrenia. Mol Psychiatry :
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
Georgiev, Danko; Yoshihara, Toru; Kawabata, Rika et al. (2016) Cortical Gene Expression After a Conditional Knockout of 67 kDa Glutamic Acid Decarboxylase in Parvalbumin Neurons. Schizophr Bull 42:992-1002
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

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