Long-lasting neural circuit modifications are thought to underlie all forms of adaptive and pathological experience-dependent plasticity. Thus there has been great interest in elucidating the mechanisms and functions of various forms of synaptic plasticity. While historically NMDA receptor-dependent long-term potentiation (LTP) has been the prototypic and most extensively studied form of long-lasting synaptic plasticity, it is clear that several key circuits in the mammalian brain express an NMDA receptor-independent form of LTP that is triggered by increases in cAMP and mediated by a long-lasting enhancement of neurotransmitter release. The central goal of this program project is to elucidate the molecular mechanisms and functions of this presynaptic form of LTP. This will be accomplished by analyzing the functional properties of the presynaptic active zone protein RIM to both presynaptic forms of plasticity as well as its contribution to learning and memory in the cerebellum. We have assembled four projects to accomplish these goals. In project #1, we propose a biochemical and genetic analysis of RIM to elucidate the contributions that individual RIM isoforms and domains make to RIM function. In project #2, we will utilize electrophysiological approaches to assess the physiological functions of RIM isoforms and discrete RIM domains to different forms of presynaptic plasticity. In project #3, we propose a set of cellular and dynamic imaging studies to examine how RIM proteins regulate the dynamics of key active zone proteins in response to synaptic activity. Finally, in project #4, we proposed to integrate these RIM structure function studies to assess the role that presynaptic forms of plasticity contribute to VOR plasticity in the mouse cerebellum. These studies will advance our understanding of not only how RIM proteins regulate neurotransmitter release, but also how presynaptic forms of long-lasting plasticity contribute to both neural circuit behavior and experience dependent plasticity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS053862-02
Application #
7283686
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Talley, Edmund M
Project Start
2006-09-05
Project End
2011-08-31
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
2
Fiscal Year
2007
Total Cost
$1,300,468
Indirect Cost
Name
Stanford University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Katoh, Akira; Shin, Soon-Lim; Kimpo, Rhea R et al. (2015) Purkinje cell responses during visually and vestibularly driven smooth eye movements in mice. Brain Behav 5:e00310
Shin, Soon-Lim; Zhao, Grace Q; Raymond, Jennifer L (2014) Signals and learning rules guiding oculomotor plasticity. J Neurosci 34:10635-44
Kimpo, Rhea R; Rinaldi, Jacob M; Kim, Christina K et al. (2014) Gating of neural error signals during motor learning. Elife 3:e02076
Nguyen-Vu, T D Barbara; Kimpo, Rhea R; Rinaldi, Jacob M et al. (2013) Cerebellar Purkinje cell activity drives motor learning. Nat Neurosci 16:1734-6
Baker, Steven Andrew; Chen, Lin; Wilkins, Angela Dawn et al. (2013) An AT-hook domain in MeCP2 determines the clinical course of Rett syndrome and related disorders. Cell 152:984-96
Maas, Christoph; Torres, Viviana I; Altrock, Wilko D et al. (2012) Formation of Golgi-derived active zone precursor vesicles. J Neurosci 32:11095-108
Südhof, Thomas C (2012) The presynaptic active zone. Neuron 75:11-25
Arons, Magali H; Thynne, Charlotte J; Grabrucker, Andreas M et al. (2012) Autism-associated mutations in ProSAP2/Shank3 impair synaptic transmission and neurexin-neuroligin-mediated transsynaptic signaling. J Neurosci 32:14966-78
Waites, Clarissa L; Leal-Ortiz, Sergio A; Andlauer, Till F M et al. (2011) Piccolo regulates the dynamic assembly of presynaptic F-actin. J Neurosci 31:14250-63
Grabrucker, Andreas M; Garner, Craig C; Boeckers, Tobias M et al. (2011) Development of novel Zn2+ loaded nanoparticles designed for cell-type targeted drug release in CNS neurons: in vitro evidences. PLoS One 6:e17851

Showing the most recent 10 out of 22 publications