Neuronal development and synapse formation requires coordinated signaling to orchestrate pre- and post-synaptic maturation of synaptic connections. With the long-term goal of identifying novel activity-dependent synaptic growth mechanisms that are triggered by seizures and neuronal plasticity, we propose to use Drosophila as a model system for characterizing the molecular mechanisms by which enhanced neuronal activity drives synaptic growth. We will characterize how the reception and transmission of activity-dependent synaptic growth signals occurs at a specialized region of the presynaptic terminal known as the periactive zone. In particular, we will determine how F-BAR proteins function at periactive zones to modulate actin assembly and membrane deformation to trigger endocytosis and trafficking of activated synaptic growth signaling receptors in an activity-dependent fashion. It is widely appreciated that excessive neuronal activity during epileptic states reinforces synaptic wiring circuits that lead to unstable recurrent connections that make seizure attacks more frequent and severe. An understanding of activity-dependent rewiring mechanisms is also important in pediatric epilepsy, where differences between the immature and mature brain result in unique pathophysiology and consequences of seizures. Increased excitability in the immature brain can lead to irreversible alterations in neuronal connectivity. Here, we propose to take advantage of a host of genetic manipulations available in Drosophila to characterize the cellular and molecular mechanisms by which enhanced neuronal activity couples to modifications of synaptic connectivity and circuit rewiring.

Public Health Relevance

Activity-dependent changes in brain function and connectivity occur in response to excessive neuronal firing during seizure episodes. Excessive neuronal activity during epileptic states reinforces synaptic wiring circuits that lead to unstable recurrent connections that make seizure attacks more frequent and severe. We propose to use Drosophila as a model system to explore the cellular and molecular mechanisms by which enhanced neuronal activity couples to modifications of synaptic connectivity during epilespy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS043244-09
Application #
8238354
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Whittemore, Vicky R
Project Start
2002-04-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
9
Fiscal Year
2012
Total Cost
$360,150
Indirect Cost
$145,775
Name
Massachusetts Institute of Technology
Department
Miscellaneous
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
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