They synapsins are a family of brain-specific synaptic vesicle-enriched phosphoproteins that regulate neurotransmitter release by tethering synaptic vesicle to active zones. Recently a variety of in vitro studies have indicated that these molecules also have trophic effects on the elongation on axons and the formation of synapses. The presence of synapsins accelerates the elongation of axons and the formation of synapses, while cultures of neurons lacking the synapses have a retarded rate of axon elongation and synapses. To determine if the synapsins act as trophic agents in vivo, we will examine mice lacking the various synapsins. We will compare the rate and degree of synapse formation in wild-type and synapsin-deficient mice. We will also examine changes in the degree of synapse loss with aging in synapsin-deficient mice. Hippocampal CA1 pyramidal neurons undergo cyclic dendritic spine sprouting and pruning during oestrus and following estrogen priming. The present studies will seek to determine if female mice lacking synapsins undergo similar degrees of synaptogenesis. Experiments will examine the granule cell mossy fiber sprouting that accompanies kindling, an experimental model of epilepsy, in mice lacking synapsin. The degree of sprouting will be quantified and compared between wild-type and synapsin-deficient mice. Studies will examine the rate and degree of sertonergic fiber regeneration following chemical lesions in wild-type and synapsin-deficient mice. Studies indicate that at least some of the actions of certain neurotrophic agents (e.g. NGF and BDNF) may be mediated through the synapsins, the response of regenerating serotonin axons to growth factor stimulation will also be assessed in synapsin-deficient mice. Following lesioning of the entorhinal cortex, axons from the contralateral perforant path collateralize and innervate the deafferented dentate. This regeneration is sensitive to trophic factors and has behavioral correlates. We will examine the histological regrowth and behavioral recovery of wild-type and synapsin- deficient mice following lesions of the entorhinal cortex. Finally, age- dependent behavioral deficits will be compared in wild-type and synapsin- deficient mice. These studies should establish the trophic role of the synapsins in adult animals and should lay the groundwork for future studies aimed at elucidating the mechanisms of synapsin actions and at harnessing this trophic action in Alzheimer's disease.
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