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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH051234-17
Application #
8427376
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Panchision, David M
Project Start
1995-09-30
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
17
Fiscal Year
2013
Total Cost
$467,206
Indirect Cost
$158,236
Name
University of Pittsburgh
Department
Psychiatry
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Volk, David W; Chitrapu, Anjani; Edelson, Jessica R et al. (2015) Chemokine receptors and cortical interneuron dysfunction in schizophrenia. Schizophr Res 167:7-Dec
Lewis, David A (2014) Inhibitory neurons in human cortical circuits: substrate for cognitive dysfunction in schizophrenia. Curr Opin Neurobiol 26:22-6
Fish, Kenneth N; Hoftman, Gil D; Sheikh, Wasiq et al. (2013) Parvalbumin-containing chandelier and basket cell boutons have distinctive modes of maturation in monkey prefrontal cortex. J Neurosci 33:8352-8
Volk, David W; Radchenkova, Polina V; Walker, Erin M et al. (2012) Cortical opioid markers in schizophrenia and across postnatal development. Cereb Cortex 22:1215-23
Fish, Kenneth N; Sweet, Robert A; Lewis, David A (2011) Differential distribution of proteins regulating GABA synthesis and reuptake in axon boutons of subpopulations of cortical interneurons. Cereb Cortex 21:2450-60
Hoftman, Gil D; Lewis, David A (2011) Postnatal developmental trajectories of neural circuits in the primate prefrontal cortex: identifying sensitive periods for vulnerability to schizophrenia. Schizophr Bull 37:493-503
Lewis, David A (2011) The chandelier neuron in schizophrenia. Dev Neurobiol 71:118-27
Beneyto, Monica; Lewis, David A (2011) Insights into the neurodevelopmental origin of schizophrenia from postmortem studies of prefrontal cortical circuitry. Int J Dev Neurosci 29:295-304
Lewis, David A (2009) Neuroplasticity of excitatory and inhibitory cortical circuits in schizophrenia. Dialogues Clin Neurosci 11:269-80
Hashimoto, Takanori; Nguyen, Quyen L; Rotaru, Diana et al. (2009) Protracted developmental trajectories of GABAA receptor alpha1 and alpha2 subunit expression in primate prefrontal cortex. Biol Psychiatry 65:1015-23

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