Overview
The Nedivi lab studies the cellular mechanisms that underlie activity-dependent plasticity in the developing and adult brain. Their approach is to identify and characterize participating genes and the functions of the proteins they encode. This work began with the cloning of a large number of candidate plasticity genes (CPGs) that are activity regulated. The first two of these CPGs selected for in-depth analysis were cpg2 and cpg15, based on their expression and regulation patterns and the sub-cellular localization of their gene products.

Research Summary
CPG2: The CPG2 protein shares homology to the spectrin/dystrophin family of structural proteins. Proteins of the spectrin family are critical components of the submembrane cytoskeleton found in most eukaryotic cells, supporting their structural integrity and serving additional functions, such as protein sorting and targeting. The Nedivi lab found that CPG2 is specifically localized to excitatory postsynaptic sites on dendritic spines. Within spines CPG2 interacts with the actin cytoskeleton and is associated with vesicle-like structures near sites of clathrin-coated pit formation adjacent to the postsynaptic density. The Nedivi has also identified proteins that are involved in vesicular trafficking as potential CPG2-binding partners. These data suggest that CPG2 may play a role in protein trafficking at glutamatergic spine synapses. The hypothesis currently being tested is that CPG2-bearing vesicles are involved in delivery or cycling of specific proteins (such as glutamate receptors) to and/or from the synapse.

CPG15: cpg15 encodes a small highly conserved protein with a secretion signal and a consensus sequence for membrane attachment through a GPI link. Consistent with its isolation as an activity-regulated gene, late cpg15 expression is contemporaneous with critical periods for activity-dependent plasticity, and is dependent on action potential activity. Its overexpression at these times results in coordinated growth of dendritic and axonal arbors, and synaptic maturation. The Nedivi lab has recently shown that CPG15 is also expressed in an activity-independent manner in regions of the embryonic brain that are undergoing rapid proliferation and apoptosis. Cellular knockdown of endogenous CPG15 by intraventricular injection of a lentivirus-delivered small hairpin RNA results in increased apoptosis of embryonic cortical neurons in vivo. CPG15 is the first identified factor expressed by neuroblasts and shown to be essential for their survival. The Nedivi lab has proposed that, like the neurotrophic factors BDNF, NGF, and NT3, CPG15 plays a dual role in the nervous system. It functions as both a survival factor that rescues cells from apoptosis, and as a growth and differentiation factor that affects process outgrowth and synaptic maturation. In addition to acting as a target derived survival factor like the neurotrophins, soluble CPG15 protects specific neuronal progenitor populations during morphogenesis of the mammalian forebrain, countering early apoptosis in a balance that regulates brain size and shape. To study CPG15 function during these two different phases of brain development the Nedivi lab is creating cpg15 knockout mice with temporally and spatially restricted deletions.

Structural plasticity in the adult brain: Many CPGs are capable of modifying neuronal structure, suggesting that neuronal structure can be modified by activity even in the adult brain. To investigate the molecular mechanisms underlying structural plasticity in the mammalian brain the Nedivi lab in collaboration with Dr. So’s group in the Dept. of Mechanical Engineering at MIT has developed a multi-photon microscope system for chronic in vivo imaging of neuronal morphology in the intact rodent cerebral cortex. Using this system they have imaged and reconstructed the dendritic trees and axon collaterals of neurons in visual cortex of thy1-GFP transgenic mice. These transgenic mice express GFP in a random subset of neurons sparsely distributed within the superficial cortical layers that are optically accessible through surgically implanted cranial windows. The images show an abundance of detail, with the basal and apical dendrites instantly recognizable and spines clearly visible. This enables dendritic branch dynamics in individual neurons to be examined over several months. Repeated imaging has revealed dendritic structural remodeling, consistent with the idea that it is a substrate for adult plasticity. Different morphological classes of neurons show different remodeling dynamics, suggesting that cell-type specific rules influence circuit rearrangement.

Selected Publications
Putz, U., Harwell, C., and Nedivi, E. Soluble CPG15 expressed during early development rescues cortical neurons from apoptosis. Nature Neurosci. 8, 322-331. (2005)

Cottrell, J.R., Borok, E., Horvath, T.L., and Nedivi, E. CPG2:A brain- and synapse-specific protein that regulates the endocytosis of glutamate receptors. Neuron, 44, 677-690. (2004)

Fujino, T., Lee, W. A. and Nedivi, E. Regulation of cpg15 by signaling pathways that mediate plasticity. Mol. Cell Neurosci. 24, 538-554. (2003)

Search PubMed for Nedivi lab publications.