Prefrontal cortex (PFC) dysfunction is a fundamental aspect of the pathophysiology of schizophrenia. Understanding the mechanisms that contribute to this dysfunction has been hindered by the scarcity of animal models that study the relationship between specific clinical features of the illness and PFC pathology in dynamic and behaviorally relevant contexts. Many studies of this relationship in humans have focused on altered metabolic activation of dorsal regions of prefrontal cortex (PFC) which provide mechanistically vague measures because they primarily provide an index of presynaptic activity, independent of whether this presynaptic activity results in postsynaptic excitation, inhibition, or modulation. Thus, translating the findings of human imaging studies to electrophysiological and other mechanistic studies in laboratory animals has been difficult. In the past few years, two separate lines of evidence have begun to provide clues about the mechanisms that may contribute to the dysfunction of PFC in schizophrenia. These include "static" measures in postmortem tissue showing reductions in the markers of GABA synthesis and "dynamic" measures in behaving individuals that report abnormal oscillatory neuronal activity during behavioral engagement in individuals with schizophrenia. Although these findings have been theoretically linked, there is no clear evidence that reduced GABA synthesis in the PFC is a potential cause of impaired oscillatory activity and cortical dysfunction. The overarching aim of this project is to establish a relationship between reduced GABA synthesis in the PFC, disruptions in oscillatory activity of PFC neurons, and cognitive functioning. Using ensemble recordings and pharmacological manipulations in rats engaged in cognitive tasks dependent on the functional integrity of PFC we will address two specific hypotheses: (1) that reduced GABA synthesis in the PFC impairs cognitive functioning and disrupts the dynamics of neuronal activity in this region by reducing GABA availability and (2) that this disruption occurs at "multi- scale" levels meaning that we will observe changes in single neuron and neuron-pair interactions, local field potential (LFP) oscillations, and phase synchrony between single units and LFP oscillations.

Public Health Relevance

Schizophrenia is a major public health problem because it affects nearly 1% of population. Present methods of treating this disorder are suboptimal. The present study aims to provide mechanistic insight about this disease which may help with the discovery of better treatments.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
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Rossi, Andrew
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University of Pittsburgh
Schools of Arts and Sciences
United States
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Pehrson, Alan L; Bondi, Corina O; Totah, Nelson K B et al. (2013) The influence of NMDA and GABA(A) receptors and glutamic acid decarboxylase (GAD) activity on attention. Psychopharmacology (Berl) 225:31-9
Totah, Nelson K B; Jackson, Mark E; Moghaddam, Bita (2013) Preparatory attention relies on dynamic interactions between prelimbic cortex and anterior cingulate cortex. Cereb Cortex 23:729-38
Moghaddam, Bita; Javitt, Daniel (2012) From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology 37:4-15
Kim, Yunbok; Wood, Jesse; Moghaddam, Bita (2012) Coordinated activity of ventral tegmental neurons adapts to appetitive and aversive learning. PLoS One 7:e29766