A subset of GABA neurons in the dorsolateral prefrontal cortex (DLPFC) is altered in subjects with schizophrenia. The affected neurons include parvalbumin (PV)-containing chandelier neurons whose axon terminals form vertical arrangements (""""""""cartridges"""""""") that synapse exclusively on the axon initial segment (AIS) of pyramidal cells. Networks of PV-containing GABA neurons give rise to gamma band oscillations, and impairments in working memory function in schizophrenia are accompanied by reductions in DLPFC gamma band power. Thus, alterations in PV-containing chandelier neurons may play a critical role in the pathophysiology of working memory dysfunction in schizophrenia. Understanding this role requires knowledge of the normal development of chandelier neurons during adolescence, the typical age of onset of schizophrenia. In the monkey DLPFC, the densities of chandelier axon cartridges immunoreactive (IR) for PV or the GABA membrane transporter (GAT1) markedly decline during adolescence. Because reductions in PV and GAT1 increase the release and efficacy of GABA in response to repetitive stimuli, a decline during adolescence in PV and GAT1 in cartridges may substantially enhance the chandelier neuron regulation of pyramidal cell output, and contribute to the maturation of working memory performance. Thus, the proposed studies are designed to determine whether the normal maturation of monkey DLPFC chandelier neurons during adolescence strengthens their ability to regulate pyramidal cell output and to synchronize the activity of larger groups of pyramidal cells at gamma frequencies.
Aims 1 -3 tests the hypothesis that adolescence is associated with decreased PV and GAT1 proteins in cartridges, and Aim 4 tests the hypothesis that these changes are associated with an increased efficacy of chandelier neuron inputs to pyramidal cells under the repetitive firing present during working memory tasks.
Aim 5 examines changes in chandelier cells during adolescence that may increase their ability to generate gamma oscillations, and Aim 6 tests the hypothesis that gamma band power in the DLPFC increases during adolescence. The strengths of the proposed studies include the integration of anatomical, molecular and electrophysiological techniques in a primate model system to explore the cellular and circuitry bases for the normal maturation of working memory performance and to inform the pathophysiology of working memory dysfunction in schizophrenia.
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