The long term goal of our laboratory is to understand at a cellular/molecular level how neuronal activity regulates the formation and maturation of synapses during brain development, and ultimately to use genetic model systems to understand how defects in this developmental process lead to cognitive dysfunction. It has been well established that cognitive development depends upon experience-driven changes in the number and strength of synaptic connections between neurons in the brain. It is also known that neuronal activity drives the transcription of a number of gene products, many of which function at synapses. These data raise the possibility that neuronal activity may drive plasticity in part by modulating the intrinsic gene expression program that directs synaptic development. However the key transcriptional regulators of synaptogenesis and how the products of activity-inducible gene transcription modulate synaptic development remain largely unknown.
Our laboratory is taking two approaches to this problem. First we are studying the molecular mechanisms by which extrinsic factors like neuronal activity regulate intrinsic gene expression programs through the modulation of transcription factor function and chromatin structure. Second, we are studying the role of neural activity and activity-dependent expression of the neurotrophin Brain-Derived Neurotrophic Factor in GABAergic synaptogenesis. In both contexts we are using culture-based assays and RNA interference to characterize the transcriptional regulators and signaling pathways that direct synaptic development. In the future, mice bearing mutations of these proteins may be good candidates to provide animal models for complex disorders of cognitive and emotional development such as mental retardation and autism.
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