Multiple autism genes influence GABA neuron remodeling via distinct developmental trajectories

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Over 100 genes are linked to autism risk, but their specific roles in neurodevelopment and behavior remain unclear.
• Previous research focused on early neurodevelopmental steps, with limited investigation into later stages, circuit function, plasticity, and behavior.

Purpose of the Study:

• To screen conserved autism-associated genes for their impact on experience-dependent neuron remodeling and circuit plasticity in C. elegans.
• To identify novel regulators and molecular mechanisms underlying these processes and their connection to autism.

Main Methods:

• Screened twenty conserved autism-associated genes for effects on the DVB neuron's neurite outgrowth in adult C. elegans.
• Assessed impact on DVB-regulated spicule protraction behavior.
• Utilized a metric geometry computational framework (CAJAL) to analyze DVB morphology data.

Main Results:

• Loss of specific genes (e.g., unc-44/ANK2, set-4/KMT5B) altered DVB neurite outgrowth, with distinct temporal effects.
• Multiple autism genes influenced DVB-regulated behavior, but only a subset overlapped with morphology findings.
• The CAJAL framework identified additional genes impacting DVB morphology and behavior, including unc-2/CACNA1A and unc-10/RIMS1.

Conclusions:

• Identified novel regulators of experience-dependent neuron remodeling and circuit plasticity.
• Demonstrated the utility of C. elegans behavioral circuits for screening conserved autism genes.
• Strengthened the link between conserved autism genes and neural circuit development/plasticity.