The long-term goal of this project is to identify molecular mechanisms that regulate the stability and plasticity of dendritic spines, small postsynaptic structures that play key roles in signal processing in neuronal circuits. Disruptions of spine numbers and shape occur in many neurological and neuropsychiatric diseases, including mood disorders, autism, and neurodegenerative disease. The size and shape of spines correlates with the physiological strength of the synapse, thus understanding the key molecular pathways that regulate spine shape and stability are crucial for designing therapies to combat such cognitive diseases. This project will focus on a central molecular pathway controlling spine shape and stability that involves the protein MARCKS. Using quantitative fluorescence imaging in dissociated cultures of rodent neurons, the project will characterize the function of MARCKS in dendritic spines using cellular and molecular approaches. Project objectives are to identify the interaction of MARCKS with downstream effectors and their influence on actin filaments and synaptic protein assemblies.

Public Health Relevance

The long-term goal of this project is to identify molecular mechanisms that regulate the stability and plasticity of dendritic spines, small postsynaptic structures that play key roles in signal processing in neuronal circuits. Disruptions of spine numbers and shape occur in many neurological and neuropsychiatric diseases, including mood disorders, autism, stroke, and neurodegenerative disease. The size and shape of spines correlates with the physiological strength of the synapse, thus understanding the key molecular pathways that regulate spine shape and stability are crucial for designing therapies to combat such cognitive diseases. This project will focus on a central molecular pathway controlling spine shape and stability that involves the protein MARCKS and the signaling phospholipid PIP2. Using quantitative fluorescence imaging in dissociated cultures of rodent neurons, the project will characterize the function of MARCKS in dendritic spines using cellular and molecular approaches. Project objectives are to identify the interaction of MARCKS with downstream effectors and their influence on actin filaments and synaptic protein assemblies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH087823-05
Application #
8585884
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Asanuma, Chiiko
Project Start
2009-12-04
Project End
2014-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
5
Fiscal Year
2014
Total Cost
$336,360
Indirect Cost
$113,610
Name
University of California San Diego
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Calabrese, Barbara; Saffin, Jean-Michel; Halpain, Shelley (2014) Activity-dependent dendritic spine shrinkage and growth involve downregulation of cofilin via distinct mechanisms. PLoS One 9:e94787
Platholi, Jimcy; Herold, Karl F; Hemmings Jr, Hugh C et al. (2014) Isoflurane reversibly destabilizes hippocampal dendritic spines by an actin-dependent mechanism. PLoS One 9:e102978
Sinnar, Shamim A; Antoku, Susumu; Saffin, Jean-Michel et al. (2014) Capping protein is essential for cell migration in vivo and for filopodial morphology and dynamics. Mol Biol Cell 25:2152-60
Calabrese, Barbara; Halpain, Shelley (2014) Lithium prevents aberrant NMDA-induced F-actin reorganization in neurons. Neuroreport 25:1331-7
Dehmelt, Leif; Poplawski, Gunnar; Hwang, Eric et al. (2011) NeuriteQuant: an open source toolkit for high content screens of neuronal morphogenesis. BMC Neurosci 12:100