Dendritic spines receive most excitatory synaptic inputs in the brain, and undergo activity-dependent structural changes associated with synaptic plasticity, learning and memory. While changes in the actin cytoskeleton are known to contribute to spine structural remodeling, little attention has been given to the role of microtubules (MTs) in these processes because spines have historically been thought to be devoid of MTs. Recently, MTs have been shown to enter spines in a dynamic, activity-dependent manner, suggesting that they may contribute to post-synaptic plasticity. The proposed experiments will determine the contribution of MTs to spine structural plasticity during long-term potentiation (Aim 1), determine whether MT dynamics are locally regulated by synaptic activity and internal calcium (Aim 2), and determine the contribution of MTs to spine structural plasticity during homeostatic synaptic plasticity (Aim 3). Because almost nothing is currently known about the function of MTs in spines, these studies have the potential to uncover completely novel mechanisms for activity-dependent spine reorganization. This work will have important clinical implications because changes in the dynamics of MTs in dendrites and spines may contribute to abnormal spine and synapse phenotypes associated with degenerative disorders (e.g. Alzheimer's disease), developmental disorders (e.g. Fragile X Syndrome), and psychiatric disorders (e.g. schizophrenia). PUBLIC HEALTH RELEVANCE: Many pathologies of the nervous system, such as Alzheimer's disease and Fragile X Syndrome, alter the structure and motility of dendritic spines and also affect microtubule stability in neurons. This study will determine the contribution of dynamic microtubules to spine morphological plasticity, and will therefore have important implications for diseases that may affect spines, either directly or indirectly, through alterations in microtubule stability.