Normal cognitive processing, i.e. learning and memory consolidation, requires physical remodeling of synaptic connections. This remodeling commonly manifests as changes in dendritic arborization and alterations in the size, shape and density of dendritic spines. Since spines represent the site for excitatory synaptic inputs, modification of spine properties translates into changes in the efficacy of synaptic communication.  Not surprisingly, abnormalities in dendritic arborization and spinogenesis, which diminish neuronal connectivity, are a common feature of the cognitively compromised aging brain as well as numerous forms of mental retardation including Fragile X, Fetal alcohol, Downs and Rett syndromes.

It is clear that changes in synaptic activity and neurotrophic factors (e.g., BDNF) are effective initiators of the remodeling process and result in long-term alterations in dendrite and spine structure. What is not known are the molecular mechanisms that underlie how they stimulate dendritic spine formation.figure

The primary focus of our lab's research is to determine the molecular and cellular mechanism by which synaptic activity and neurotrophic factors influence neuronal development. Our lab and others have demonstrated that synaptic activity and BDNF increase both intracellular calcium and the transcription of a subset of CREB-dependent genes, both of which are required to promote rearrangement of the cytoskeleton and the formation of dendritic spines. We use a multidisciplinary approach combining disruption of key signaling cascades using dominant negative and constitutively active mutants, genetic manipulations and pharmacology with live imaging and confocal microscopy as well as both molecular and biochemical techniques to evaluate the roles of different CREB regulated gene products in regulating neuronal structural plasticity. As an outcome of our research we hope to determine the key CREB controlled genes activated by synaptic activity and BDNF, which regulate of neuronal morphogenesis, and to determine how they shape the development and modification of dendritic spines. In understanding the molecular players involved in these processes, one may in the future be able to develop therapies to treat neuronal developmental and/or psychiatric disorders. Thus our studies have strong implications for underlying causes of mental diseases.