MOUSE MODEL OF HYPERKINESIA IMPLICATES SNAP-25 IN BEHAVIORAL-REGULATION

Although hyperkinesis is expressed in several neurological disorders, the biological basis of this phenotype is unknown. The mouse mutant co loboma (Cm/+) exhibits profound spontaneous locomotor hyperactivity re sulting from a deletion mutation. This deletion encompasses several ge nes including Snap, which encodes SNAP-25, a nerve terminal protein in volved in neurotransmitter release. Administration of amphetamine, a d rug that acts presynaptically, markedly reduced the locomotor activity in coloboma mice but increased the activity of control mice implicati ng presynaptic function in the behavioral abnormality. In contrast, th e psychostimulant methylphenidate increased locomotor activity in both coloboma and control mice. When a transgene encoding SNAP-25 was bred into the coloboma strain to complement the Snap deletion, the hyperac tivity expressed by these mice was rescued, returning these corrected mice to normal levels of locomotor activity. These results demonstrate that the hyperactivity exhibited by these mice is the result of abnor malities in presynaptic function specifically attributable to deficits in SNAP-25 expression.