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
Melom, Jan E; Littleton, J Troy (2013) Mutation of a NCKX eliminates glial microdomain calcium oscillations and enhances seizure susceptibility. J Neurosci 33:1169-78
Weiss, Kurt R; Kimura, Yoko; Lee, Wyan-Ching Mimi et al. (2012) Huntingtin aggregation kinetics and their pathological role in a Drosophila Huntington's disease model. Genetics 190:581-600
Guan, Zhuo; Buhl, Lauren K; Quinn, William G et al. (2011) Altered gene regulation and synaptic morphology in Drosophila learning and memory mutants. Learn Mem 18:191-206
Rodal, Avital A; Blunk, Aline D; Akbergenova, Yulia et al. (2011) A presynaptic endosomal trafficking pathway controls synaptic growth signaling. J Cell Biol 193:201-17
Schulte, Joost; Littleton, J Troy (2011) The biological function of the Huntingtin protein and its relevance to Huntington's Disease pathology. Curr Trends Neurol 5:65-78
Schulte, Joost; Sepp, Katharine J; Wu, Chaohong et al. (2011) High-content chemical and RNAi screens for suppressors of neurotoxicity in a Huntington's disease model. PLoS One 6:e23841
Wu, Chaohong; Schulte, Joost; Sepp, Katharine J et al. (2010) Automatic robust neurite detection and morphological analysis of neuronal cell cultures in high-content screening. Neuroinformatics 8:83-100
Schulte, Joost; Sepp, Katharine J; Jorquera, Ramon A et al. (2010) DMob4/Phocein regulates synapse formation, axonal transport, and microtubule organization. J Neurosci 30:5189-203
Rodal, Avital A; Motola-Barnes, Rebecca N; Littleton, J Troy (2008) Nervous wreck and Cdc42 cooperate to regulate endocytic actin assembly during synaptic growth. J Neurosci 28:8316-25
Mattaliano, Mark D; Montana, Enrico S; Parisky, Katherine M et al. (2007) The Drosophila ARC homolog regulates behavioral responses to starvation. Mol Cell Neurosci 36:211-21

Showing the most recent 10 out of 12 publications