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Regulation of synaptogenesis by cyclin-dependent kinase 5  

Most of the genes that have been associated with autism appear to regulate how neurons communicate with each other at structures called synapses. Mutations in the genes associated with autism appear to disrupt synapse formation, which may account for the social, language and intellectual impairments often associated with the disorder. Li-Huei Tsai and her colleagues at the Massachusetts Institute of Technology plan to study the role of cyclin-dependent kinase 5 (CDK5), an enzyme involved in synapse activity, and its influence on SHANK3, another protein known to be important in autism. They also plan to study how CDK5 influences inhibitory interneurons, which control the excitability of neural circuits. CDK5 can regulate the activities of proteins by marking them with phosphate groups. In neurons, loss of CDK5 reduces the electrophysiological response after an activating signal, leading to fewer synapses and impaired learning in mice. Tsai and her colleagues have shown that CDK5 phosphorylates the synaptic protein SHANK3, as well as other proteins in the synapse. They have shown that CDK5 plays a crucial role in inhibitory interneurons in the brain, specifically in parvalbumin-expressing (PV+) neurons that control the excitability of target neurons and maintain synaptic homeostasis. The absence of CDK5 in these neurons leads to behavioral abnormalities in mice, which include including stereotypic behavior and cognitive impairment. Tsai's group proposes that CDK5 may be a master regulator of pathways that controls the creation and function of synapses, and that these pathways may be disrupted in autism. The researchers are testing this hypothesis by studying how CDK5's removal affects synapse structure and activity. They have developed experimental strategies to study CDK5's role in either the sending or receiving cell of the synapse, and plan to examine the morphology and electrophysiology of CDK5-deficient neurons. With these experiments, the researchers hope to learn how the kinase regulates synapse formation, which may provide new insights into the role of synapse formation in autism. In particular, they predict that, for proper neuron activity, SHANK3 needs to be phosphorylated by CDK5 at the synapse. If this holds true, targeting phosphorylated SHANK3 to the synapse might improve neurological functioning in people with autism. In addition, given that the loss of CDK5 in interneurons leads to behavioral abnormalities in mice, targeting the activity of CDK5 may ameliorate behavioral symptoms of autism. Project Status
ONGOING

2010

Funder Simons Foundation
Fiscal Year Funding $342,454.00
Current Award Period 2008-2012
Project Number 94567
Principal Investigator Tsai, Li-Huei
Received ARRA Funding? No
Strategic Plan Question Question 2: How Can I Understand What Is Happening? (Biology)
Subcategory Molecular Pathways
Strategic Plan Objective 2O. Not specific to Question 2 objectives
Federal or Private? Private
Institution Massachusetts Institute of Technology
State/Country Massachusetts
Web Link 1 Regulation of synaptogenesis by cyclin-dependent kinase 5 (External web link)
Web Link 2 No URL available.
Web Link 3 No URL available.
New! History/Related Projects Regulation of synaptogenesis by cyclin-dependent kinase 5 | $325,889.25 | 2009 | 94567