The long-term goal of this proposal is to define molecular mechanisms that control synaptic strength. Synapses are dynamic-once formed, neural circuits evolve by the addition and elimination of synaptic connections and the modification of their strength. Setting and modifying the strength of synapses is important for refining developing circuits and defects in these mechanisms are a likely etiology of neurodevelopmental disorders such as autism and mental retardation. In the mature nervous system, modifying synaptic strength is important for normal processes such as memory formation and pathophysiological events such as the synaptic rearrangements underlying chronic pain or the synaptic loss in neurodegenerative disorders. To define molecular mechanisms that control synaptic strength, we are undertaking a genetic, anatomical, and electrophysiological analysis in Drosophila. Neurotransmitter is released from the presynaptic cell at specialized sites called active zones. Efficient synaptic transmission requires that active zones contain a normal complement of proteins, and that these specialized release sites be apposed to postsynaptic clusters of neurotransmitter receptor. Little is known of the molecular mechanisms that regulate the protein composition of active zones and ensure the alignment of neurotransmitter release and reception machinery. In screens for genes required for such processes, four mutants were identified in which a large proportion of glutamate receptor clusters are apparently unapposed to presynaptic release sites. These mutants will be characterized to uncover molecular mechanisms that form and maintain the active zone/receptor cluster dyad.

Public Health Relevance

This research is relevant to public health because it will improve our understanding of how nerve cells connect and communicate in the brain. If these connections do not form or function properly in a child, it may lead to neurological diseases such as mental retardation, epilepsy, and autism, while in the adult, loss of these connections may contribute to neurodegenerative disorders such as Alzheimer's disease. An understanding of the molecules that control the formation, function, and maintenance of nerve cell connections could aid in the future development of new therapies for devastating neurological diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS043171-07
Application #
7694344
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Talley, Edmund M
Project Start
2002-04-01
Project End
2012-08-31
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
7
Fiscal Year
2009
Total Cost
$299,250
Indirect Cost
Name
Washington University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Ehmann, Nadine; van de Linde, Sebastian; Alon, Amit et al. (2014) Quantitative super-resolution imaging of Bruchpilot distinguishes active zone states. Nat Commun 5:4650
Valakh, Vera; Naylor, Sarah A; Berns, Dominic S et al. (2012) A large-scale RNAi screen identifies functional classes of genes shaping synaptic development and maintenance. Dev Biol 366:163-71
Graf, Ethan R; Valakh, Vera; Wright, Christina M et al. (2012) RIM promotes calcium channel accumulation at active zones of the Drosophila neuromuscular junction. J Neurosci 32:16586-96
Graf, Ethan R; Heerssen, Heather M; Wright, Christina M et al. (2011) Stathmin is required for stability of the Drosophila neuromuscular junction. J Neurosci 31:15026-34
Daniels, Richard W; Miller, Bradley R; DiAntonio, Aaron (2011) Increased vesicular glutamate transporter expression causes excitotoxic neurodegeneration. Neurobiol Dis 41:415-20
Cheli, Verónica T; Daniels, Richard W; Godoy, Ruth et al. (2010) Genetic modifiers of abnormal organelle biogenesis in a Drosophila model of BLOC-1 deficiency. Hum Mol Genet 19:861-78
Graf, Ethan R; Daniels, Richard W; Burgess, Robert W et al. (2009) Rab3 dynamically controls protein composition at active zones. Neuron 64:663-77
Viquez, Natasha M; Füger, Petra; Valakh, Vera et al. (2009) PP2A and GSK-3beta act antagonistically to regulate active zone development. J Neurosci 29:11484-94
Wairkar, Yogesh P; Toda, Hirofumi; Mochizuki, Hiroaki et al. (2009) Unc-51 controls active zone density and protein composition by downregulating ERK signaling. J Neurosci 29:517-28
Wairkar, Yogesh P; Fradkin, Lee G; Noordermeer, Jasprina N et al. (2008) Synaptic defects in a Drosophila model of congenital muscular dystrophy. J Neurosci 28:3781-9

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