Candidate Plasticity Genes
To understand the cellular mechanisms that underlie activity-dependent plasticity in the developing and adult brain, we are identifying and characterizing the participating genes and the function of the proteins they encode. This work began with the cloning of a large number of activity-regulate genes that we termed candidate plasticity genes (CPGs). It turned out that the CPG pool is highly enriched for genes important for neuronal survival, connectivity, and synaptic transmission, suggesting that activity-regulated genes are critical for the development and function of brain circuits.
We have elucidated the neuronal and synaptic function of two previously unknown CPGs, CPG2 and CPG15, and characterized their very different activities, showing that each provides unique insight into diverse aspects of plasticity mechanisms. CPG2 has emerged as a key component of a specialized postsynaptic endocytic mechanism devoted to internalization of synaptic proteins, including glutamate receptors. CPG15, plays a dual role in the brain: as a survival factor that rescues cells from apoptosis, and as a growth and differentiation factor that affects process outgrowth and synaptic maturation. These two genes are still the focus of some research projects in the lab. Recently, we have returned to the CPG pool for identification of additional genes of interest.
Structural Plasticity in Cortical Circuits
Motivated by the large number of CPGs that affect neuronal structure, we have also been collaborating with Peter So’s lab in the Department of Mechanical Engineering at MIT to develop multi-photon microscopy for large volume, high resolution imaging of dendritic arbor and synaptic structural dynamics in vivo. Using this system we have chronically imaged and reconstructed the dendritic trees of neurons in visual cortex of thy1-GFP transgenic mice through surgically implanted cranial windows. Our lab was the first to show unambiguous evidence of dendritic growth and retraction and of branch tip additions in the adult brain. Surprisingly, our data singled out GABAergic interneurons as those capable of structural dynamics, suggesting that circuit rearrangement is restricted by cell type-specific rules.
By combining chronic two-photon microscopy in vivo with classic visual manipulations we showed that experience drives structural remodeling of superficial cortical layer 2/3 interneurons in an input- and circuit-specific manner. Currently we are using in vivo dual color imaging to examine different types of input onto the different excitatory and inhibitory cell types in the cortical circuit, as well as the timing of constructive and destructive events in terms of pre and postsynaptic components.
With Dr. So, we are also developing the use of high-speed microscopy (Multifocus, Multiphoton Microscopy) to aid in imaging large neuronal volumes at synaptic resolution at short time intervals. A large part of the lab is now devoted to imaging-related projects, some associated with characterization of CPG function in vivo, others asking more general questions related to structural plasticity of cortical circuitry.
Elly Nedivi received her Ph.D. in Neuroscience from Stanford University Medical School and completed her postdoctoral training at The Weizmann Institute in Israel. In 1998, after two years at Cold Spring Harbor Laboratory, she joined the faculty of the Department of Brain and Cognitive Sciences and the Picower Institute for Learning and Memory at MIT. She also has an appointment in the Department of Biology at MIT.