The brain's capacity to modify connections between neurons in response to experience is termed plasticity. Plasticity is a prominent feature of brain development and in the adult underlies learning and memory processes as well as adaptive reorganization of primary sensory maps. In the case of both developmental and adult plasticity, there is evidence that long-term synaptic changes involve activation of gene expression. Elucidating the function of such genes can provide insight into molecular and cellular mechanisms that generate plasticity at the synapse.

We have developed a highly sensitive subtractive cloning and differential screening method that has allowed us to identify and isolate a large pool of genes involved in neuronal plasticity. These approximately 315 candidate plasticity genes (CPGs) constitute the basis of our studies.

Partial sequence analysis in combination with database search programs show that 190 of the cloned CPGs encode known proteins, while approximately 125 are novel. We have used in situ hybridization to temporally and spatially localize expression of approximately 80 individual CPGs. We found many CPGs to be specific to the brain, among them a group exclusive to the hippocampal dentate gyrus (a region of the brain associated with learning and memory). Fifty CPGs were screened by two additional criteria: cortical expression during activity dependent phases of development and induction by a physiological sensory stimulus (light) specifically in the visual cortex. In a group of 30 CPGs chosen because of their expression patterns for full-length cloning and sequencing, we identified two new seven-transmembrane domain receptors, a new serine/threonine kinase, a new MAP-kinase phosphatase, a dystrophin-like cytoskeletal protein, and two potential trophic factors. This sample of CPGs demonstrates that the CPG pool contains many interesting proteins whose expression is regulated by activity. At present, there are two novel CPGs, CPG15 and CPG2, under full-scale investigation in the lab.

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CPG2 colocalizes with actin in dendritic spines. Cultured hippocampal neurons were labeled for CPG2 (blue), PSD-95 (red), and actin (green). CPG2 labeling is confined to the base of dendritic spines, where actin accumulates, suggesting an interaction between CPG 2 and the actin cytoskeleton in spines.

Fred and Carol Middleton Assistant Professor, Departments of Brain and Cognitive Sciences and Biology

Elly Nedivi received her Ph.D. in Neuroscience from Stanford University Medical School and completed her postdoctoral training at The Weitzmann Institute in Israel. In 1998, after completing research at Cold Spring Harbor Laboratory, she joined the faculty of the Department of Brain and Cognitive Sciences and the Picower Center for Learning and Memory at MIT. Dr. Nedivi is the recipient of the Ellison Medical Foundation New Scholar Award and an Alfred P. Sloan Foundation Fellowship.

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