The establishment and modulation of specific patterns of neural synaptic connectivity is crucial to normal brain function. It is likely, moreover, that abnormalities in synapse formation may, contribute to neurologic and psychiatric disorders. The overall objective of this research program is to achieve an understanding of the molecular mechanisms which underlie the regulation of genes that contribute to this process. The direct aims of the proposed investigation are to evaluate the involvement of SNAP-25, a highly evolutionary conserved presynaptic nerve terminal protein, in the spontaneous hyperactivity disorder exhibited by the mouse neurological mutant Coloboma, Cm. It is proposed that the Cm mutation in mice that encompasses a deletion of the Snap-25 gene provides a model for Attention Deficit Hyperactivity Disorder (ADHD) of children. To achieve these goals, the genomic structure and scope of the Cm mutation will be defined by analysis of restriction fragment length polymorphisms (RFLPS) of interspecies hybrids between Coloboma and Mus spretus. Probes to genes known to neighbor the Snap-25 locus and probes derived from yeast artificial chromosome (YAC) libraries will be used to identify which specific sequences are deleted and thereby map the boundaries of the Cm deletion. The second specific aim is to characterize fully the hyperactive locomotor behavior of Cm/+ mutant mice in response to psychostimulant drugs. These studies will reveal whether dopaminergic systems are involved and respond in a manner similar to that observed in ADHD.
The third aim i s to attempt to rescue the behavioral deficits of Coloboma mice through complementation by deriving transgenic animals overexpressing the gene and crossbreeding with the mutant strain.
The final aim i s to evaluate the function of Snap-25 gene expression directly in hyperactivity and behavior by specifically abolishing its expression through targeted gene disruption and reintegration into the germline of transgenic animals. Through these studies, we anticipate that a new and useful model of ADHD will be established and the possible contribution of SNAP-25 or additional factors involved in the development of hyperactivity disorders will be identified.
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