A functional nervous system requires both the appropriate development of dendritic spines and their functional plasticity throughout life. Because dendritic spines are the primary sites of contact with presynaptic axons in excitatory neurons of hippocampus and cortex, their structure and function have been studied in great detail. During development, spines undergo marked changes in structure, progressing from motile filopodial protrusions to stable mushroom-shaped spines. Activity-driven structural changes in spines of mature neurons also play important roles in learning and memory. It is therefore not surprising that changes in dendritic spines are one of the first harbingers of neuronal dysfunction in many developmental diseases, such as Fragile X syndrome and autism, as well as neurodegenerative diseases, such as Alzheimer's disease. Actin filaments play important roles in the formation, maintenance and plasticity of dendritic spine structure. Prominent in dendrite shafts, microtubules (MTs) function as stable railways for intracellular transport, but also exhibit bouts of rapid polymerization and depolymerization, termed dynamic instability. We discovered that MTs remain dynamic in dendrites throughout neuronal development and are capable of rapidly polymerizing into and out of dendritic spines in an activity-dependent fashion. In this proposal we will test the hypothesis that MT invasion of dendritic spines is a tightly regulated process resulting in motor-driven transport of cargo directly into and out of dendritic spines. Specifically, we will: 1) Determine the molecular mechanism by which MTs target specific spines, 2) Identify motor proteins and cargo that are transported into spines along MTs, and 3) Determine how material is transported out of spines along MTs. This work will provide fundamental insights into synaptogenesis and synaptic plasticity. Furthermore, because dendritic spines play essential roles in learning and memory and are the structures affected in numerous psychiatric and neurological diseases, these studies hold promise for novel cytoskeletal-based therapies for synaptic dysfunction.
Dendrites of excitatory neurons in the cortex and hippocampus maintain small protrusions along their length termed spines. Dendritic spines play an essential role in synaptic communication between neurons in the brain and the plasticity of these spines is thought to be the underlying substrate for learning and memory. Therefore, understanding the mechanisms that contribute to spine plasticity has broad implications for normal brain function and for patients suffering from intellectual and developmental disabilities (IDDs) and neurodegenerative diseases. This research will characterize a novel cytoskeletal process underlying dendritic spine plasticity.
|Dent, Erik W (2017) Of microtubules and memory: implications for microtubule dynamics in dendrites and spines. Mol Biol Cell 28:1-8|
|McVicker, Derrick P; Awe, Adam M; Richters, Karl E et al. (2016) Transport of a kinesin-cargo pair along microtubules into dendritic spines undergoing synaptic plasticity. Nat Commun 7:12741|