Research Description and Approach
Research in my laboratory focuses on mechanisms of functional plasticity in the adult central nervous system and, in particular, the roles of endogenous neurotrophic factors and integrin adhesion proteins in synaptic plasticity. Previous studies demonstrated that neuronal activity modulates the expression of genes encoding transcription and neurotrophic factors by adult forebrain neurons. Among these, brain derived neurotrophic factor (BDNF) is of particular interest because this factor is both induced with a very low activity threshold and critical for potentiation of synaptic responses by naturally occurring patterns of neuronal activity. These findings have given rise to 3 research programs:
- #1: Mechanisms of synaptic Long-Term Potentiation (LTP)
Recent studies in our laboratories and elsewhere indicate that LTP (i.e., activity-induced potentiation of synaptic responses, thought to be a cellular mechanism of learning) depends on activity-induced changes in the dendritic spine actin cytoskeleton. Current studies are exploring the cellular mechanisms through which synaptic activity modulates spine actin polymerization and the roles of these processes in the stabilization of synaptic morphology and potentiation. Studies employ acute hippocampal slice electrophysiology and both western blot and immunohistochemical analyses of signaling and actin-associated proteins in recently activated dendritic spines.
- #2: Involvement of BDNF and integrin signaling in synaptic plasticity
As noted above, BDNF is critical for LTP induced by naturally occurring levels of synaptic activity. Similarly, synaptic integrins (receptors for extracellular matrix proteins) are required for LTP consolidation. Both BDNF and the integrins signal to the actin cytoskeleton in other systems and contexts but the mechanisms through which these receptors modulate the spine cytoskeleton are not known. Current studies are testing the hypothesis that BDNF/TrkB and integrin receptor systems interact directly and through downstream intermediaries to modulate F-actin organization.
- #3: Ampakines and BDNF modulate synaptic plasticity and neuronal survival
BDNF expression is positively modulated by neuronal activity including subtle increases in activity associated with a variety of neuroactive drugs. The “ampakines” are positive modulators of AMPA-class glutamate receptor function. We have shown that ampakines can be used to stimulate and sustain increases in BDNF protein in vivo and in vitro. Coupled with evidence that BDNF supports neuronal survival and facilitates LTP, these findings suggest that ampakine treatment can be used to support neuronal viability and rescue synaptic plasticity in circumstances of neurological insult and cognitive impairment. This hypothesis is being tested in animal models of cognitive impairment and autism spectrum disorder including models of aging, Fragile-X Syndrome, and Huntington’s Disease.