Atypical sensory-based behaviors are a common feature of a number of human conditions, including autism spectrum disorder, schizophrenia, fragile X, etc. Despite this, little is known about how the genes associated with these conditions affect sensory behavior. A complete understanding of this process requires a thorough characterization of the underlying neural circuitry, along with the ability to measure and perturb the activity of these circuits. The nematode, Caenorhabditis elegans, provides a unique opportunity to analyze genes, cells, and circuits regulating complex behaviors, as its nervous system consists of just 302 neurons interconnected via identified synapses that utilize highly conserved synaptic machineries. The Chalasani lab has shown that C. elegans homologs of the human autism-associated genes (neurexin (NRX) and neuroligin (NLG)) affect sensitivity to specific sensory stimuli, and that mutations in these genes result in hyposensitivity to a repellent copper stimulus. They propose to identify the specific C. elegans synapses where these two synaptic proteins function to modify sensory behaviors. Additionally, they plan to identify the developmental time window in which these genes are required to generate a typically behaving young adult (Aim 1). Moreover, they have shown that sensory defects associated with neuroligin mutants (nlg-1) are rescued by mutations in the gene npr-1, a gene that when mutated alone results in a ?social? aggregation behavior. They propose to identify the neural mechanisms that underlie this interaction and reveal components of the NPR-1 signaling pathway that act to suppress nlg-1 behavioral defects (Aim 2). Finally, they have identified Nipecotic acid and CGP-13501 as candidate small molecules that suppress nlg-1 behavioral deficits. They plan to map the cellular and molecular targets of these drugs in C. elegans, analyzing the genetic pathways modifying NRX-1/NLG-1 signaling in this model (Aim 3). These studies will reveal mechanisms by which NRX-NLG signaling modifies sensory behavior at the level of genes, synapses, circuits, and whole animals, providing a solid foundation for further analyses in vertebrate models. As both NLG and NRX have been implicated in autism spectrum disorder, results may shed light on molecular and circuit mechanisms underlying human disorders that have been linked to abnormalities in sensory processing.

Public Health Relevance

Atypical sensitivity to sensory stimuli is a hallmark of multiple disorders including autism, schizophrenia, fragile X and others. We propose to use a simple well-defined model with conserved signaling pathways to understand how disease-associated genes like neurexin and neuroligin affect brain function. We aim to use our model to develop new early diagnostic tools and identify new targets for therapeutic intervention in these diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH096881-07
Application #
9754246
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Arguello, Alexander
Project Start
2012-12-01
Project End
2023-04-30
Budget Start
2019-05-01
Budget End
2020-04-30
Support Year
7
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
078731668
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Ibsen, Stuart; Tong, Ada; Schutt, Carolyn et al. (2015) Sonogenetics is a non-invasive approach to activating neurons in Caenorhabditis elegans. Nat Commun 6:8264
Leinwand, Sarah G; Yang, Claire J; Bazopoulou, Daphne et al. (2015) Circuit mechanisms encoding odors and driving aging-associated behavioral declines in Caenorhabditis elegans. Elife 4:e10181
Lau, Hiu E; Chalasani, Sreekanth H (2014) Divergent and convergent roles for insulin-like peptides in the worm, fly and mammalian nervous systems. Invert Neurosci 14:71-8
Leinwand, Sarah G; Chalasani, Sreekanth H (2014) From genes to circuits and behaviors: Neuropeptides expand the coding potential of the nervous system. Worm 3:e27730
Leinwand, Sarah G; Chalasani, Sreekanth H (2013) Neuropeptide signaling remodels chemosensory circuit composition in Caenorhabditis elegans. Nat Neurosci 16:1461-7