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Multiple autism genes influence GABA neuron remodeling via distinct developmental trajectories
Kristi Zoga1, Sophia Villiere1,2, Vina Tikiyani1,3
1Department of Genetics, University of Pennsylvania, Philadelphia, PA.
Researchers screened conserved autism genes in C. elegans, identifying new regulators of neuron remodeling and circuit plasticity. This study links these processes to autism risk genes and demonstrates the utility of C. elegans models for discovery.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Over 100 genes are linked to autism spectrum disorder (ASD) risk, but their precise roles in neurodevelopment and behavior remain unclear.
- Existing research often focuses on early neurodevelopmental steps, with limited investigation into later stages, circuit function, plasticity, and behavior.
- Understanding how genetic variations lead to distinct ASD-related behavioral changes requires screening conserved genes in relevant biological contexts.
Purpose of the Study:
- To screen conserved autism-associated genes for their impact on experience-dependent neuron remodeling and circuit plasticity.
- To identify novel molecular mechanisms and regulators connecting conserved autism genes to neurodevelopmental processes.
- To validate the utility of intact, behavior-generating circuits in *C. elegans* for screening autism genes.
Main Methods:
- Screened twenty conserved autism-associated genes for effects on neurite outgrowth of the GABAergic DVB neuron in adult *C. elegans*.
- Assessed the impact of gene loss on DVB neuron pre-synaptic morphology and experience-dependent remodeling.
- Utilized a computational framework (CAJAL) to analyze DVB morphology data and identify additional genes affecting neuronal structure and behavior.
Main Results:
- Loss of specific genes (*unc-44/ANK2*, *set-4/KMT5B*, *daf-18/PTEN*, *gap-2/SYNGAP1*, *chd-1/CHD8*) increased DVB neurite outgrowth, while *CACNA2D3/unc-36* decreased it.
- Identified convergent phenotypes for *daf-18/PTEN*, *set-4/KMD5B*, and *unc-44/ANK2*, but with distinct temporal impacts on DVB morphology.
- Screening for behavior (spicule protraction) and morphology identified shared genes (*unc-44/ANK2*, *CACNA2D3/unc-36*) and new candidates (*unc-2/CACNA1A*, *unc-10/RIMS1*).
Conclusions:
- This study identifies novel regulators of experience-dependent neuron remodeling and circuit plasticity, linking them to conserved autism genes.
- The findings highlight the importance of later neurodevelopmental stages and circuit function in understanding autism pathogenesis.
- Demonstrates the effectiveness of *C. elegans* behavioral circuits for screening conserved autism genes and uncovering new molecular mechanisms.
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