Elucidating Functions of the Gamma-Protocadherins in CNS Synapse Development

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DESCRIPTION (provided by applicant): Defects in the formation, patterning, maturation, and maintenance of synapses are believed to underlie a wide range of debilitating neurological and psychiatric disorders, including autism, Alzheimer's disease, mental retardation, and schizophrenia. Understanding and, potentially, ameliorating such disorders will thus depend on identifying the molecules that control synapse development. The long term goal of this work is to understand how adhesion molecules promote the establishment and specificity of synaptic connections, and the present application is focused on one family of such molecules, the y-protocadherins (Pcdhs), that are prime candidates for such roles. Preliminary studies have shown that mice in which the 22-member Pcdh-y gene family is deleted die shortly after birth with severe neurological abnormalities due to interneuron synapse loss and neurodegeneration in the spinal cord. Pcdh-y mutant spinal interneurons exhibit fewer and physiologically weaker synaptic connections even when neurodegeneration is blocked genetically. Critical questions about the precise roles played by the v-Pcdh family of proteins remain unanswered, however, and will be addressed by the two specific aims of this proposal. First, the specificity and dynamics of v-Pcdh synaptic localization will be determined by: 1) examining the localization of v-Pcdh proteins to distinct types of synapses in intact CMS tissues at multiple developmental stages; and 2) using time-lapse confocal microscopy of hippocampal slice cultures expressing fluorescently-tagged y-Pcdhs to follow the dynamics of their localization to spine synapses during maturation. Second, specific functions of the v-Pcdhs in synapse formation, maturation, and maintenance will be determined by: 1) crossing tissue-specific Cre mouse lines with mice harboring two conditional Pcdh-y mutant alleles to developmental^ disrupt v-Pcdh function in discrete neuronal populations not addressable previously, including cortical, hippocampal, and sensory neurons; and 2) crossing a tamoxifen-inducible Cre mouse line with conditional Pcdh-y mutant mice to allow temporally controlled disruption of y-Pcdh function in mature neurons after they have formed synapses. Together, these studies will define synaptic functions for the diverse v-Pcdh family of proteins and identify the neuronal circuits in which they act, thus providing critical tools needed to investigate the exciting possibility that individual v-Pcdh isoforms serve as cues to specify appropriate pre- and post-synaptic partners. As aberrant patterning of synaptic connections is likely to underlie many cognitive, emotional, and behavioral deficits in humans, studies such as those described herein will benefit public health by contributing to the basic science foundation needed for the development of new therapeutic approaches in the future.