NMDA Receptors and GABA neurons in schizophrenia

Mc Lean Hospital (Belmont, Ma), Belmont MA

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Abstract

DESCRIPTION (provided by applicant): Schizophrenia is one of the most severe psychiatric disorders, affecting about 1% of the population worldwide. Recent research has consistently documented that neurocognitive deficits are pervasive features of this illness. Furthermore, they are increasingly recognized as the most important determinants of long-term functional outcome of patients suffering from schizophrenia. Unfortunately, the efficacy of all of the currently available antipsychotic medications in the treatment of these deficits is modest at best. Successful treatment of these deficits would profoundly impact the course of schizophrenia and the quality of life of patients suffering from this illness. Many of the neurocognitive deficits observed in schizophrenia, such as working memory and executive functioning impairments, reflect disturbances of information processing in the prefrontal cortex (PFC). Information processing in the PFC is modulated by gamma-aminobutyric acid (GABA) ergic local circuit neurons. Importantly, activities of these latter neurons are also regulated by glutamatergic inputs. Therefore, either direct disturbances of GABAergic local circuit neurons or abnormal glutamatergic modulation of these neurons could contribute to information processing deficits in the cerebral cortex in schizophrenia. In either scenario, it is conceivable that information processing deficits could potentially be functionally normalized by pharmacologically calibrating the activities of glutamatergic modulation of GABA neural circuitry. In spite of this potentially important therapeutic implication, currently, relatively little is known about the nature of glutamatergic modulation of GABA neural circuitry in the PFC in schizophrenia. In the proposed studies, a double in situ hybridization technique, combining the use of radioactive and non-radioactive riboprobes in the same experiment, will be used to begin to explore this important issue by examining the expression of the mRNA for the NMDA NR1, NR2A, or NR2B glutamate receptor subunits, which have all been implicated in the pathophysiology of schizophrenia, in GABAergic local circuit neurons that contain the GABA synthesizing enzyme glutamic acid decarboxylase (GAD)67 mRNA in the PFC in schizophrenia.