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Name:	E. Christopher Muly
Position:	Assistant Professor of Psychiatry and Behavioral Sciences Affiliate Scientist of Yerkes National Primate Research Center
Degree:	M.D., Duke University, 1993 Ph.D., Duke University, 1992
Programs:	NS, Associate Member MSP, Associate Member
Phone:	404 727-9603
Address:	Yerkes National Primate Center, 954 N. Gatewood Dr., 2440/001/1AA
Email:	ecmuly@rmy.emory.edu
Research Descriptions:
Short:	Structural basis for cortical function; circuitry of the prefrontal cortex.
Long:	My primary research interest is in the structural basis of the functioning of the neocortex. In particular, I am examining the relationship between the circuitry of the cerebral cortex and the molecular components of neurotransmission, neurotransmitter receptors and signal transduction proteins. In this way, I hope to shed light on the basis both of neuropsychiatric disorders and of drug action in the central nervous system. Currently, I am focusing on the D1 dopamine receptor and its relation to circuitry and other neurotransmission proteins in the primate prefrontal cortex. Working memory function depends on an intact dopaminergic projection to the prefrontal cortex and in particular on stimulation of the D1 receptor. Both too much and too little D1 receptor stimulation results in impaired working memory function. Patients with schizophrenia manifest impairments in working memory and other prefrontal cortical functions as well as alterations in dopaminergic neurotransmission and evidence for abnormal circuitry in prefrontal cortex. A better understanding of the interaction between prefrontal circuitry and the dopamine system may suggest novel treatments for this illness. We are using neuroanatomical tract tracers to label different components of prefrontal circuitry in macaque monkeys, including inputs from the thalamus, parietal cortex and local axons. We then use double label immunohistochemical techniques and electron microscopic analysis to determine if the labeled axons synapse onto structures that contain the D1 receptor. Previous work has shown that dopamine acting at D1 receptors enhances glutamate-gated currents, and in primate prefrontal cortex, D1 is located on dendritic spines, in close proximity to excitatory, glutamatergic synapses. Identifying the class of axons that synapse onto D1 containing spines will suggest aspects of prefrontal circuitry that are particularly relevant to working memory function. The D1 dopamine receptor belongs to the class of G-protein coupled receptors; all effects of D1 stimulation are mediated by signal transduction proteins. The D1 receptor is coupled, via Gs to an increase in cAMP levels and a signal transduction pathway that included protein kinase A, DARPP-32 and protein phosphotase-1 (PP1). We have expanded our investigations to include components of this pathway. PP1 exists in multiple isoforms in the brain including alpha and gamma-1. Recently, we have shown that dendritic spines in prefrontal cortex can be divided into populations based on their content on these two isoforms, and that the D1 receptor is associated with one of these populations. This finding suggests that dendritic spines do not possess identical signal transduction capabilities, a possibility that has implications for other G-protein coupled receptors and for the inputs that target these spines. We are also studying the relationship between cortical circuitry and PP1-defined spine populations with the same methods described above for the D1 receptor. In addition, we are exploring the significance of the multiple isoforms of PP1 by using post-embedding immunolabeling to determine whether the different PP1 isoforms are localized to different compartments within individual spines. Finally, we hope to extend these finding to other components of the Gs signal transduction pathway and to other G-protein coupled receptors.