@entity4677 accelerates the onset of supply rate XXXX in synaptic vesicle trafficking.

@entity4677 @entity308 @entity19 @entity71526 @entity29279 @entity2049 @entity302 @entity734
OBJECTIVE: To determine if @entity4677 ( @entity29279 ) enhances the impact in excitatory presynaptic terminals of a rate-limiting mechanism in vesicle trafficking termed supply rate @entity308 that emerges to limit synaptic transmission during heavy, epileptiform use. METHODS: The effect of @entity29279 was measured with electrophysiologic assays of monosynaptic connections in ex vivo hippocampal slices from wild-type and synapsin knockout @entity19 , and in primary cell culture neurons from wild-type and @entity71526 ( @entity71526 ) knockout @entity19 . RESULTS: @entity29279 enhanced the impact of supply rate @entity308 at Schaffer collateral synapses by shortening the time course for induction. The @entity29279 effect was selective for supply rate @entity308 because other presynaptic vesicle trafficking mechanisms were not affected. The half maximal effective concentration (EC50 ) was ~50   m. The maximal effect was ~15  % and occurred at 100   m, which is a clinically relevant concentration. An experimental protocol is established for distinguishing atypical @entity734 ( @entity734 ) that affect supply rate @entity308 , such as @entity29279 , from typical @entity734 , such as @entity2049 , that affect upstream mechanisms. The @entity29279 effect was abolished at synapses from knockout @entity19 lacking @entity71526 and from synapses lacking synapsin 1 and 2. SIGNIFICANCE: The findings are consistent with the new hypothesis that @entity29279 acts to treat @entity302 by accelerating the induction of supply rate @entity308 at excitatory synapses during incipient @entity302 activity. The absence of the effect in the knockouts confirms that presynaptic function is the target. More specifically, the absence in @entity71526 knockouts is consistent with previous binding studies suggesting that @entity71526 is the target for @entity29279 . The absence in synapsin knockouts indicates that the phenotypic target intersects with the biochemical pathway that is altered in synapsin knockouts. The results from synapsin knockouts additionally suggest that development of functional analogs with increased potency might be possible because induction of supply rate @entity308 is faster in synapsin knockouts compared to wild-type synapses treated with @entity29279 .
