Project 4

Neuronal basis of sensory processing dysfunction in schizophrenia

Project 4 aims to:

• Use stereological cell counting methods to measure the density of different GABA cell types as a percentage of the total cortical neuron density in samples of sensory cerebral cortex from subjects diagnosed with schizophrenia and age-matched non-psychiatric control human postmortem brains.
• Evaluate cell density and morphology in monkeys chronically treated with phencyclidine (PCP) as a pharmacological model of schizophrenia
• Assess mRNA expression levels within identified pyramidal neurons, calbindin (CB)-immunoreactive and parvalbumin (PV)-immunoreactive GABAergic interneurons within the auditory cortex in the schizophrenia and age-matched control cohort
• Compare mRNA expression in the same identified cell types in PCP, haloperidol, and saline treated monkeys

This project examines cell density and gene expression profiles of GABA-ergic interneurons in primary visual cortex in schizophrenia, using laser capture microdissection coupled with gene array expression techniques developed by the Principal Investigator, Dr. Ginsberg, and builds as well from a prior gene array study of hippocampal stellate cells in schizophrenia showing reduced NMDA receptor-related expression.  The Co-Investigator, Dr. Smiley, is an expert histologist who is pursuing ongoing studies of calcium binding protein/GABA interneuron density in auditory cortex as part of an NIMH-funded project. 

Decreased parvalbumin expression has been extensively documented in prefrontal cortex in schizophrenia, but sensory regions have been studied to only a limited degree.  For the NKI component of the study, quantitative morphometric analyses are performed on postmortem visual cortex from schizophrenia and control subjects.  Immunocytochemistry is used to identify GABA interneuron cell types, including pavalbumin, calbindin and calretinin cell types.  Relative density of GABA interneurons are then compared between schizophrenia and control groups.  Finally, using laser capture microdissection, select populations of calbindin and parvalbumin neurons are obtained and processed for gene array analysis by Dr. Ginsberg.  Gene array analysis analyzes expression level of calcium binding proteins, glutamate-related constructs and other more general gene families.

Investigators: Stephen Ginsberg, PhD (Principal Investigator), John Smiley, PhD (Co-Principal Investigator)