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Elly Nedivi
Using the powerful techniques of molecular biology, Professor Elly Nedivi's lab aims to unravel which of the brain's genes are involved in making memories, and to detail how they work. Building this fundamental understanding of how the brain works may eventually help scientists design highly targeted drugs for treating disorders like Alzheimer's.
The basis of our lab's studies are 362 genes that may be involved in the phenomenon of "plasticity." Approximately 240 of these candidate plasticity genes (CPGs) are novel. All these activity-regulated genes were isolated using a highly sensitive subtractive cloning and differential screening method. To assess how interesting each CPG is, how closely related it may be to plasticity and whether there are hints as to its function that could aid in its characterization, we are applying various selection criteria such as sequence homologies and motifs, temporal and spatial expression patterns, and regulation by physiological activity in the context of plasticity paradigms.
One of the first CPGs we selected for full-scale characterization is CPG15, a small molecule that can promote exuberant dendritic arbor growth in developing neurons through an intercellular signaling mechanism. Our model for CPG15 action, based on immunocytochemistry and in situ hybridizations, proposes that CPG15 supplied by presynaptic neurons promotes dendritic arbor growth in their postsynaptic partners. This model predicts the existence of a CPG15 receptor (CPG15R) on cells responding to CPG15's growth promoting activity. Currently in the lab, CPG15 is being used as bait to try and fish out the CPG15R. Our main approach to testing CPGs' participation in cellular events related to plasticity involves manipulating their expression using virally mediated gene transfer. The effect of cellular manipulation is then monitored by confocal microscopy for changes in neuronal morphology, or electrophysiologically for changes in synaptic properties. Ultimately, we will use gene "knock out" experiments to assess the effect of specific CPGs on brain development, as well as adult cortical plasticity. The first tissue-specific CPG "knock out" will be that for CPG15.
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