The central hypothesis of our Center focuses on critical disturbances in the regulation of cognition and behavior in schizophrenia that reflect functional abnormalities in the intrinsic circuitry of the dorsolateral prefrontal cortex (DLPFC) and in its interconnections with other brain regions. These functional disturbances are hypothesized to arise during posnatal development as a consequence of alterations in the molecular signals and structural elements that determine synaptic efficacy in the affected neural circuits. These alterations include somatodendritic morphological abnormalities, such as smaller somal volumes, decreased dendritic arbor size and complexity, and reduced dendritic spine density, of pyramidal neurons, the principal excitatory projection neurons of the neocortex. Furthermore, these somatodendritic abnormalities in schizophrenia may be specific to, or at least present to a greater degree in, a subset of pyramidal neurons. Because a neuron' s dendritic arbor is a maj or determinant of its functional circuit properties, pyramidal neuron somatodendritic abnormalities, in concert with related synaptic disturbances, may be central to DLPFC-mediated cognitive dysfunction in schizophrenia. Consequently, knowledge of the specific subsets of pyramidal neurons that are affected in schizophrenia is essential for determining both the potential causes of these abnormalities and their contributions to disturbed DLPFC information processing. Thus, using an integration of experiments in postmortem human brain specimens and in nonhuman primates, the studies proposed in this project are designed to determine 1) the laminar location(s) of the DLPFC pyramidal neurons that exhibit somatodendritic abnormalities in schizophrenia; 2) the molecular phenotypes of pyramidal neurons that furnish different types of extrinsic projections in monkey DLPFC; 3) the somatodendritic integrity of molecularly-identified subpopulations of DLPFC pyramidal neurons in schizophrenia; and 4) the molecular mechanisms that may contribute to developmental somatodendritic changes in monkey DLFPC pyramidal neurons. These investigations have a number of conceptual and technical links with other Center projects and depend upon support provided by all of the proposed cores.
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