The precise control of synaptic connectivity is essential to coordinated neural function. Underscoring this importance, a variety of neurological and neuropsychiatric disorders -including epilepsy, intellectual disability, autism and schizophrenia-are thought to arise at least in part from alterations in synaptogenesis and maintenance. New approaches to the prevention and treatment of these disorders will depend on a fuller understanding of the mechanisms by which the developing nervous system specifies and remodels synapses. Interestingly, many of these disorders exhibit pronounced sex bias in incidence and severity, suggesting that sex-specific properties of neural connectivity could contribute to their etiology. Here, we take advantage of recently described sexual dimorphisms in tail sensory circuitry of the nematode C. elegans to identify mechanisms by which synapse specification and maintenance are modulated according to an individual's biological sex. In this exploratory pilot project, our goals are two-fold. First, we will develop tools using a recently-described fluorescent labeling strategy to allow the visualization of sexually dimorphic connectivity in tail sensory circuitry in living nematodes. Second, we will use these reagents to ask several exploratory questions that will allow us to generate specific, testable mechanistic hypotheses. In particular, we will study the timing with which sexual dimorphisms are established and will identify specific cellular foci through which genetic sex modulates synaptogenesis. Ultimately, this exploratory project will provide a basis for generating hypotheses about molecular mechanisms that may contribute to understanding sexually dimorphic neural connectivity and circuit function across the animal kingdom.

Public Health Relevance

The normal function of the human brain critically depends on the connections between its roughly 100 billion neurons. Many neurological and neuropsychiatric disorders- including epilepsy, autism, schizophrenia and intellectual disability-arise at least in part through the disruption of these connections. In this pilot study, we will develop tools in a small, simple nematode to help dissect the genetic mechanisms that control the regulated formation and maintenance of these connections. Ultimately, these studies should help shed light on the genetic bases for a variety of disorders of the nervous system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS082849-01
Application #
8489524
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Morris, Jill A
Project Start
2013-04-01
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$191,875
Indirect Cost
$66,875
Name
University of Rochester
Department
Genetics
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Fagan, Kelli A; Portman, Douglas S (2014) Sexual modulation of neural circuits and behavior in Caenorhabditis elegans. Semin Cell Dev Biol 33:3-9