Disturbances in certain cognitive functions are among the most debilitating and persistent symptoms of schizophrenia, and convergent lives of evidence indicate that these symptoms reflect dysfunction of the dorsolateral prefrontal cortex (DLPFC). Postmortem investigations of schizophrenic subjects suggest that this dysfunction may be associated with abnormalities in 1) afferents from the mediodorsal thalamic nucleus (MDTN) which terminate in layers deep 3 and 4; 2) pyrimidal cells located in layer 3; and 3) the chandelier class of GABA interneurons which provide inhibitory input to the axon initial segment of the pyramidal cells. However, understanding the functional significance and potential pathophysiological relationships of these abnormalities requires an appreciation of the roles that each of these neural elements play in the normal functional architecture of the DLPFC. The studies funded during the current grant period focused on the intrinsic excitatory circuitry furnished by layer 3 pyramidal cells, using the macaque monkey DLPFC as a model of the human. We found that these neurons give rise to horizontal axon collaterals that reciprocally link clusters of layer 3 pyramidal cells, arrayed as a series of stripes. A given group of interconnected stripes appears to form a discrete module that may serve to form a discrete modules that may sere to recruit and/or coordinate the activity of spatially-segregated groups of pyramidal cells. Differences across the cortex in the features of these horizontal connections suggest that they contribute to the regional specialization of function. Consequently, we hypothesize that the connectivity within a DLPFC module plays a central in the mediation of cognitive processes, such as working memory, that are disturbed in subjects with schizophrenia. In the proposed studies of monkey DLPFC an integrated set of anatomical and in vitro electrophysiological techniques will be used to test hypotheses regarding 1) the relationships between DLPFC modules (as defined by horizontal, intrinsic connection) and the organization of afferent inputs from the MDTN; 2) the shaping of the functional properties of a given stripe by within-stripe interactions between pyramidal cells and certain classes of GABA interneurons, including chandelier cells; and 3) the extent to which the reciprocal, intrinsic connections between stripes form unique modules. The results of these studies will inform our understanding of the normal functional architecture of the primate DLPFC, and will guide the conduct and interpretation of studies of DLPFC circuitry in schizophrenia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH051234-07
Application #
6528769
Study Section
Special Emphasis Panel (ZRG1-IFCN-8 (01))
Program Officer
Anderson, Kathleen C
Project Start
1995-09-30
Project End
2004-07-31
Budget Start
2002-08-01
Budget End
2003-07-31
Support Year
7
Fiscal Year
2002
Total Cost
$239,547
Indirect Cost
Name
University of Pittsburgh
Department
Psychiatry
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Dienel, Samuel J; Bazmi, Holly H; Lewis, David A (2017) Development of transcripts regulating dendritic spines in layer 3 pyramidal cells of the monkey prefrontal cortex: Implications for the pathogenesis of schizophrenia. Neurobiol Dis 105:132-141
Miyamae, Takeaki; Chen, Kehui; Lewis, David A et al. (2017) Distinct Physiological Maturation of Parvalbumin-Positive Neuron Subtypes in Mouse Prefrontal Cortex. J Neurosci 37:4883-4902
Hoftman, Gil D; Datta, Dibyadeep; Lewis, David A (2017) Layer 3 Excitatory and Inhibitory Circuitry in the Prefrontal Cortex: Developmental Trajectories and Alterations in Schizophrenia. Biol Psychiatry 81:862-873
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Volk, David W; Edelson, Jessica R; Lewis, David A (2016) Altered expression of developmental regulators of parvalbumin and somatostatin neurons in the prefrontal cortex in schizophrenia. Schizophr Res 177:3-9
Volk, David W; Lewis, David A (2016) The Role of Endocannabinoid Signaling in Cortical Inhibitory Neuron Dysfunction in Schizophrenia. Biol Psychiatry 79:595-603
Hoftman, Gil D; Volk, David W; Bazmi, H Holly et al. (2015) Altered cortical expression of GABA-related genes in schizophrenia: illness progression vs developmental disturbance. Schizophr Bull 41:180-91
Volk, David W; Chitrapu, Anjani; Edelson, Jessica R et al. (2015) Molecular mechanisms and timing of cortical immune activation in schizophrenia. Am J Psychiatry 172:1112-21
Rotaru, Diana C; Olezene, Cameron; Miyamae, Takeaki et al. (2015) Functional properties of GABA synaptic inputs onto GABA neurons in monkey prefrontal cortex. J Neurophysiol 113:1850-61

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