Stress-induced neuron remodeling reveals differential interplay between neurexin and environmental factors

Abstract

Neurexins are neuronal adhesion molecules important for synapse maturation, function, and plasticity. Neurexins have been genetically associated with neurodevelopmental disorders including autism spectrum disorders (ASDs) and schizophrenia, but can have variable penetrance and phenotypic severity. Heritability studies indicate that a significant percentage of risk for ASD and schizophrenia includes environmental factors, highlighting the poorly understood interplay between genetic and environmental factors in pathogenesis of these disorders. The singular C. elegans ortholog of human neurexins, nrx-1, controls experience-dependent morphologic remodeling of a GABAergic neuron in adult males. Here I show that this GABAergic neuron's morphology is altered in response to each of three environmental stressors (nutritional, heat, or genotoxic stress) applied during sexual maturation, but not during adulthood. Increased outgrowth of axon-like neurites following adolescent stress results from an altered morphologic plasticity that occurs upon entry into adulthood. Despite axonal remodeling being induced by each of the three stressors, only nutritional stress (starvation) impacts behavior and is dependent on neurexin/nrx-1. Heat or genotoxic stress during sexual maturation did not alter behavior despite inducing GABAergic neuron remodeling, and this remodeling was independent of neurexin/nrx-1. Remodeling induced by starvation stress was found be dependent on neuroligin/nlg-1, the canonical binding partner for neurexin/nrx-1, as well as the stress signaling transcription factors FOXO/daf-16 and HSF1/hsf-1, each of which was also found to have unique roles in remodeling induced by heat and UV stress. The differential molecular mechanisms underlying GABAergic neuron remodeling in response to different stressors, and the disparate effects of stressors on behavior, is a novel paradigm for understanding how genetics, environmental exposures, and plasticity may contribute to brain dysfunction in ASDs and schizophrenia.