Neurophysiological Studies of Schizophrenia

Harvard Medical School, Boston MA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by the applicant0: This submission is a competitive Revision of RO1 MH040799 in response to Notice NOT-OD-09-058 [NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications]. This revision addresses the following NIMH area of interest - Translational Science: Innovative Targets and Models for Developing Treatments for Mental Disorders. The overall goal is the creation of an in vitro animal model of high frequency (gamma band;approx 40Hz) neocortical oscillations allowing us to test the neurobiological model underlying our clinical work documenting the developmental timecourse of gamma band abnormalities in schizophrenia (Sz) patients (Specific aim 1 in the parent grant). Such gamma band abnormalities are thought to be responsible for executive function deficits in Sz and at present there are few therapeutic approaches to treat these aspects of the disease. The approach of the parent (clinical) grant and the current competitive revision is based on our neurobiological model: abnormal gamma band oscillations in Sz result from a developmentally regulated alteration in neocortical circuitry involving N-methyl-D-aspartate (NMDA) receptors on interneurons leading to defective recurrent inhibition of cortical pyramidal neurons. We focus here on one neocortical area, the prelimbic cortex (PrL), which is the murine homolog of the dorsolateral prefrontal cortex in humans. This area is implicated in executive function deficits in Sz and has been identified as a target area for NIMH Recovery Act funds. Clinical postmortem data have identified abnormalities in GABAergic interneurons in prefrontal and other areas in brains from schizophrenic patients, in particular fast-spiking interneurons responsible for recurrent inhibition and containing the calcium binding parvalbumin (PV). To study the role of these GABAergic neurons in neocortical gamma band oscillations we will use mice expressing green fluorescent protein (GFP) under the control of the GAD67 promoter (GFP mice), allowing on line identification of GABAergic neurons prior to recording. Whole-cell recordings will be made from PV-positive neurons identified initially by their fastspiking behavior and confirmed by post-hoc labeling. Blockade of NMDA receptors with the psychomimetic ketamine or selective NMDA receptor subtype antagonists will be used to test our hypothesis of an NMDA (specifically NR2A) receptor abnormality being responsible for gamma abnormalities. Pharmacological agents (kainate, carbachol) will be used to generate gamma band oscillations in PrL brain slices in vitro. Male or female mice at different ages [pre-pubertal (14-24 d), adolescent (35-45 d), adult (81-91 d)] will be used to test developmental and sex differences in (i) power and frequency of gamma oscillations (ii) subtype of NMDA receptors on interneurons and (iii) the effect of chronic ketamine. We believe a deeper understanding of the ontogenesis of the cellular and molecular elements involved in generating neocortical gamma rhythms will lead eventually to treatments which can alleviate executive function deficits in Sz. DESCRIPTION (provided by applicant): Schizophrenia is a major mental illnesses that causes its'victims and their families much anguish and is a major source of lost productivity and medical care expenses to our nation. The parent grant for this revision involves a longitudinal study of defective brain oscillations in the 40 Hz (gamma) range in schizophrenic patients. This competitive revision proposal is centered around the generation of an in vitro animal model allowing us to test our hypotheses of the neurons and neurotransmitter receptors responsible for the development of abnormal gamma oscillations in this disease.