The goal of this work is to understand the functions of synaptic plasticity in terms of its cellular contexts: the neuronal wiring diagram, the astrocytic modulatory system, the vascular support system, and subcellular modulatory and modification processes. (1) Synaptic plasticity will be elicited behaviorally either by novel experience in the form of a complex (or """"""""enriched"""""""" laboratory) environment or by a specific forelimb motor training task. Electron microscopic studies are proposed to elucidate the effects of these experiences at a wiring diagram level to ask if plasticity is specific to particular afferent systems (e.g., thalamic vs. cortical in motor learning), or particular synaptic subtypes (e.g., excitatory vs. inhibitory, spine vs. shaft). Light microscopic studies of axons are proposed to determine whether axons are likely to connect with new neurons and whether they add branches in the process of forming new connections. Parallel electrophysiological studies are proposed to assess the functional correlates of structural changes and to determine if structural and functional changes are consistently associated across afferent systems. (2) A finding that opens new possibilities is our discovery that the fragile X mental retardation protein is translated under neurotransmitter control in a synaptoneurosome preparation. Because we believe this process may play a role in plastic morphological and behavioral change, we propose to use a recently developed mouse model with the fragile X gene """"""""knocked out"""""""" to determine whether equivalent (to wild type) morphological plasticity and behavioral plasticity in response to experience occurs in the absence of the function of the fragile X gene. Studies are also proposed to examine the spatiotemporal relationships between experience-triggered synaptogenesis, determined electron microscopically, and fragile X protein expression, determined immunocytochemically, using the complex environment model. Expression of select other proteins that may also participate in synaptic plasticity will also be examined in this model. Finally, the persistence of morphological effects of experience is to be studied in the absence of continued differential experience or training. These studies address cellular mechanisms underlying learning and memory, recovery from damage to the nervous system and experience-related aspects of syndromes such as schizophrenia and depression.
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