The core cognitive deficits of schizophrenia are present and progressive well before the illness is typically diagnosed in young adults, and thus represent an important target for novel pharmacological approaches for disease-modifying, early interventions. The working memory component of these deficits reflects impaired gamma band (30-80 Hz) oscillations in the dorsolateral prefrontal cortex (DLPFC) that appear to be due, at least in part, to alterations in specific inhibitory circuits. In particular, gamma oscillations require strong and fast inhibitory inputs from fast-spiking, parvalbumin-containing (PV+) basket cells to pyramidal neurons;in schizophrenia, markers of both pre- and post-synaptic components of PV+ basket cell to pyramidal cell connections are altered in the DLPFC. However, little is known about the development of the structural, molecular or electrophysiological properties of PV+ basket cell to pyramidal cell connections during the protracted maturation of the primate DLPFC. Our preliminary findings suggest that different features of the inputs from PV+ basket cells to the soma of pyramidal neurons exhibit distinctive trajectories that may define sensitive periods in DLPFC circuitry development. Consequently, the proposed studies integrate innovative methods to identify the developmental trajectories in the monkey DLPFC of the structural (Aim 1) and molecular (Aim 2) determinants, and the resulting electrophysiological indices (Aim 3), of the strength of PV+ basket cell inputs to pyramidal neurons;the molecular determinants (Aim 4), and the resulting electrophysiological indices (Aim 5), of the speed or kinetics of these inputs;and 3) the expression of gene products in PV+ and pyramidal neurons that influence the functional properties of these inputs (Aim 6). The developmental trajectories identified in these studies will define sensitive periods in DLPFC development during which selective manipulations of the number, strength or kinetics of PV+ basket cell inputs to pyramidal cells (conducted in future in vivo studies) are likely to have acute and/or persistent effects on gamma band power and working memory performance not seen with the same manipulations at other stages of development. Such knowledge will inform the most appropriate type and timing of early pharmacological interventions in individuals vulnerable for schizophrenia. Thus, this application directly addresses NIMH Strategic Plan Strategy 1.1 Determine the mechanisms and course of brain development and how this maps onto behavior;and Strategy 2.1 Determine how periods of change in development may also be periods of vulnerability for the emergence of risk or symptoms.

Public Health Relevance

Advances in the ability to identify individuals at risk for schizophrenia has created an opportunity for developing novel, disease-modifying, early interventions. The proposed studies will define the developmental trajectories of key components of prefrontal cortical circuitry that are altered in schizophrenia. These studies will delineate sensitive periods during prefrontal cortical development when pharmacological interventions in individuals vulnerable for schizophrenia might have the greatest reward, or risk, potential.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Developmental Brain Disorders Study Section (DBD)
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Panchision, David M
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University of Pittsburgh
Schools of Medicine
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Pafundo, Diego E; Miyamae, Takeaki; Lewis, David A et al. (2018) Presynaptic Effects of N-Methyl-D-Aspartate Receptors Enhance Parvalbumin Cell-Mediated Inhibition of Pyramidal Cells in Mouse Prefrontal Cortex. Biol Psychiatry 84:460-470
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
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
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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
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
Volk, David W; Chitrapu, Anjani; Edelson, Jessica R et al. (2015) Chemokine receptors and cortical interneuron dysfunction in schizophrenia. Schizophr Res 167:12-7

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