David Lewis, PhD

Professor
Department of Psychiatry
University of Pittsburgh
Pittsburgh, Pennsylvania
February 12, 2007

Dissecting the Disease Process of Schizophrenia: Role of Cortical GABA Neurons

Critical cognitive deficits in schizophrenia, such as impairments in working memory (the ability to transiently keep in mind a limited amount of information in order to guide thought or behavior) are associated with dysfunction of the dorsolateral prefrontal cortex (DLPFC). Postmortem investigations indicate that these cognitive deficits might reflect alterations in the expression of certain genes in specific populations of GABAergic, inhibitory neurons in the DLPFC. In particular, the specific combination of gene expression abnormalities seen in illness converge on the idea that the synthesis of GABA is reduced in the chandelier class of GABA neurons that furnish inhibitory inputs exclusively to the axon initial segment of excitatory pyramidal neurons. This deficit in GABA neurotransmission is associated with an up-regulation of GABAA receptors that contain alpha 2 subunits, which are preferentially localized to pyramidal neuron axon initial segments. Chandelier neurons play a critical role in regulating the synchronization or timing of pyramidal neuron firing during working memory. Thus, these findings suggest that the alterations in chandelier neurons in schizophrenia represent a pathological entity that gives rise to the disturbances in neural synchrony observed clinically in association with working memory impairments in schizophrenia. Reduced neurotrophin signaling via the trkB receptor appears to be a pathogenetic mechanism underlying these abnormalities. Parallel studies in genetically engineered mice support these conclusions. Together, these findings suggest that a medication that enhances GABAergic neurotransmission only at pyramidal neuron axon initial segments and that preserves the normal timing of chandelier neuron activity would improve working memory function and clinical outcome in individuals with schizophrenia.

 

 

 

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