What changes occur in the brain when we learn and how is the new information stored? Memories appear to be encoded as changes in the strength of specific synaptic connections while their stabilization is achieved by changes in gene expression.
Specifically, the CREB family of transcription factors is one of the core components in the molecular switch that converts short- to long-term memory. Angel Barco, the proposed Team leader, joined the group of Dr. Kandel at Columbia Univ. and generated a number of lines of mutant mice in the CREB activation pathway to gain new insights into its function.
He used recent technical advances in mouse genetics that allow restricting, both anatomically and temporally, the expression of a genetic alteration. This allowed a precise examination of the role of CREB in hippocampal synaptic plasticity and spatial memory.
A first study describing one of these lines of genetically modified mice, published in Cell, provided important insights into the molecular mechanisms of synaptic-specific potentiation and the role of transcription in this process; several manuscripts describing other aspects of these mice phenotype are in preparation.
Now, together with the Instituto de Neurociencias (Spain), he proposes to continue and extent these studies with the analysis of other mutant mice in this pathway, applying a multidisciplinary approach that combines molecular biology, mouse genetics and behaviour with electrophysiology.
The goal of this proposal is deciphering the genetic programs required for long-lasting synaptic plasticity, learning and memory. This knowledge may reveal how dysfunction of these molecular processes leads to neurological disorders and open new therapeutics avenues for restoring normal brain function, indeed this may be the case for Huntington disease (HD).
A new therapeutic approach based on the neuro-protective role of CREB will be tested in mouse models for HD as a part of this proposal.
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