This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This work relates prefrontal cortical circuitry with the molecular components of dopamine neurotransmission. The results will be related to the circuitry of working memory, which is dysfunctional in schizophrenia. Working memory function depends on an optimal level of D1 receptor activation and is impaired by both over and under stimulation of D1 receptor. It is hoped that our results will lead to a better understanding of the mechanism of the D1 receptor's complex modulation of working memory, and ultimately to a better understanding of antipsychotic drug action. We will identify the source of afferents that terminate onto spines that contain D1 and protein phosphatase-1 (PP1) isoforms PP1(alpha) and PP1(gamma)1. We have injected neuroanatomical tract tracers into the brains of young adult macaque monkeys to label parietal, thalamic and posterior cingulate afferents to prefrontal cortex, and within prefrontal cortex to label local horizontal axons. We are using double-labeling techniques appropriate for electron microscopy to stain the labeled axons and either D1, PP1(alpha) or PP1(gamma)1. We are using serial section electron microscopy to determine if the postsynaptic targets of labeled axons contain these proteins. The distribution of these proteins subdivides cortical spines, and the results will suggest aspects of cortical circuitry that are critical for working memory function and extend our understanding of the mechanisms by which cortical circuitry may be specialized. We have used post-embedding immunogold labeling to examine the distribution of PP1 targeting proteins (spinophilin and neurabin) and PP1(alpha) and PP1(gamma1) in spines. Our date indicates that the D1 receptor has access to different complements of signal transduction proteins in different neuronal compartments and suggests functional differences for the two PP1 isoforms. Finally we have used single and pre-embedding double label methods to examine the subcellular localization of group I mGluRs (mGluR1a and mGluR5) and determined a number of differences in their distribution, both between each other, between monkey cortex and rat cortex and between cortex and basal ganglia. The funding for this project ended in August of 2005 and it is currently in a no cost extension year.
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