SYNAPTOGENESIS AFTER ISCHEMIC BRAIN INJURY

Washington University, Saint Louis MO

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Abstract

DESCRIPTION (From the applicant's abstract): Synapses in the central nervous system are selectively vulnerable to ischemic brain injury, and this damage may be critical to neurologic dysfunction after stroke. Little is known of the fate of synapses that are lost, even when the neurons that connect them survive. To examine this process, we have developed a culture model that allows continuous observation of individual post-synaptic dendritic spines and presynaptic terminals in mouse cortical neurons. Transient deprivation of oxygen and glucose causes rapid, glutamate receptor-dependent loss of dendritic spines and synaptic terminals followed by their return within hours. We hypothesize that functional new synapses are formed after sublethal injury and that this occurs by recapitulation of developmental pathways. Synaptic structure and function will be assessed by confocal microscopy and electrophysiology. The long-term goal is to improve neurological function after stroke. Using dissociated cultures of murine cortical neurons, we will examine the time course and electrophysiology of synaptogenesis after injury (Aim 1), assess the role of calcium-dependent cytoskeletal reorganization (Aim 2), and determine the effects of extracellular influences (astrocytes, estradiol, and trophic factors) known to promote synaptogenesis during development (Aim 3). Finally, we will determine whether mechanisms of synapse loss and recovery found in dissociated cultures apply to intact slices from adult mouse cortex or hippocampus, maintained up to 12 hours after sublethal oxygen-glucose deprivation (Aim 4). The long-term goal is to identify strategies to improve neurological function after stroke.