Signaling networks that control synapse development and cognitive function.

Experience plays a crucial role in the development of the nervous system by promoting the maturation, and elimination of synapses. We have found that synaptic stimulation by promoting calcium influx into neurons regulates a complex gene program that controls aspects of synapse development. We have identified a signaling network that conveys the calcium signal from the site of entry to the nucleus where transcription is activated. Of the activity-regulated genes, brain derived neurotrophic factor (BDNF) is one of the best characterized. Studies of BDNF gene regulation indicate the presence of a repressor complex bound to the BDNF promoter prior to stimulation that becomes replaced by an activator complex in stimulated cells. Mutations in MeCP2 a component of the BDNF repressor complex lead to Rett Syndrome an X linked human disorder marked by severe cognitive and motor impairment. Mutations in additional components of the activitydependent signaling network also lead to cognitive impairment in humans indicating a critical role for this gene program in controlling normal cognitive function