CREB and the discovery of cognitive enhancers.

In the past few years, a series of molecular-genetic, biochemical, cellular and behavioral studies in fruit flies, sea slugs and mice have confirmed a long-standing notion that long-term memory formation depends on the synthesis of new proteins. Experiments focused on the cAMP-responsive transcription factor, CREB, have established that neural activity-induced regulation of gene transcription promotes a synaptic growth process that strengthens the connections among active neurons. This process constitutes a physical basis for the engram--and CREB is a "molecular switch" to produce the engram. Helicon Therapeutics has been formed to identify drug compounds that enhance memory formation via augmentation of CREB biochemistry. Candidate compounds have been identified from a high throughput cell-based screen and are being evaluated in animal models of memory formation. A gene discovery program also seeks to identify new genes, which function downstream of CREB during memory formation, as a source for new drug discoveries in the future. Together, these drug and gene discovery efforts promise new class of pharmaceutical therapies for the treatment of various forms of cognitive dysfunction.