Autism gene variants disrupt enteric neuron migration and cause gastrointestinal dysmotility.

The comorbidity of autism spectrum disorders and severe gastrointestinal symptoms is well-established, yet the molecular underpinnings remain unknown. The identification of high-confidence large-effect autism risk genes offers the opportunity to identify convergent, underlying biology by studying these genes in the context of the gastrointestinal system. Here we show that the expression of these genes is enriched in human prenatal gut neurons as well as their migratory progenitors, suggesting that the development and/or function of these neurons may be disrupted by autism-associated pathogenic variants, leading to gastrointestinal dysfunction. Here we document the prevalence of gastrointestinal issues in patients with large-effect variants in sixteen of these genes, highlighting dysmotility, consistent with potential enteric neuron dysfunction. Using the high-throughput diploid frog Xenopus tropicalis , we individually target five of these genes ( SYNGAP1, CHD8, SCN2A, CHD2 , and DYRK1A ) and observe disrupted enteric neuronal progenitor migration for each. More extensive analysis of DYRK1A reveals that perturbation causes gut dysmotility in vivo , which can be ameliorated by treatment with a selective serotonin reuptake inhibitor (escitalopram) or a serotonin receptor 6 agonist, identified by in vivo drug screening. This work suggests that atypical development of enteric neurons contributes to the gastrointestinal distress commonly seen in individuals with autism and that increasing serotonin signaling may be a productive therapeutic avenue.

Pleiotropy of autism-associated chromatin regulators.

Gene ontology analyses of high-confidence autism spectrum disorder (ASD) risk genes highlight chromatin regulation and synaptic function as major contributors to pathobiology. Our recent functional work in vivo has additionally implicated tubulin biology and cellular proliferation. As many chromatin regulators, including the ASD risk genes ADNP and CHD3, are known to directly regulate both tubulins and histones, we studied the five chromatin regulators most strongly associated with ASD (ADNP, CHD8, CHD2, POGZ and KMT5B) specifically with respect to tubulin biology. We observe that all five localize to microtubules of the mitotic spindle in vitro in human cells and in vivo in Xenopus. Investigation of CHD2 provides evidence that mutations present in individuals with ASD cause a range of microtubule-related phenotypes, including disrupted localization of the protein at mitotic spindles, cell cycle stalling, DNA damage and cell death. Lastly, we observe that ASD genetic risk is significantly enriched among tubulin-associated proteins, suggesting broader relevance. Together, these results provide additional evidence that the role of tubulin biology and cellular proliferation in ASD warrants further investigation and highlight the pitfalls of relying solely on annotated gene functions in the search for pathological mechanisms.

Brain Camp: A Summer Pipeline Program to Increase Diversity in Neurosciences.

BACKGROUND: Despite calls to increase diversity in the health care workforce, most medical fields including neurology have seen minimal advances, owing in part to the lack of developing a robust pipeline for trainees from underrepresented backgrounds. We sought to create an immersive, replicable neurology-themed summer camp and longitudinal mentorship program for underrepresented-in-medicine (URM) high-school students to encourage them to enter the training pipeline in neuroscience-related fields. METHODS: We established an annual, no-cost 1-week camp for local URM students with the goals of exposing them to different health care professions within neuroscience while providing them with college application resources and long-term mentorship. A postprogram survey was distributed to assess the students' attitudes towards the camp and their desires to pursue health care careers. RESULTS: Over the 4 years since the founding of the camp (2016-2020), a total of 96 students participated, of whom 53% were URM, 74% came from very low-income households, and 61% had parents who did not attend college. In total, 87 students (91%) completed the postcamp survey. Nearly all (97%) of the respondents were likely to recommend the camp to their peers, and the vast majority (85%) felt that Brain Camp made them more likely to pursue careers in health care. CONCLUSIONS: Brain Camp seeks to address the unmet need for low barrier-to-entry programs designed for URM high-school students interested in health care careers. We envision that our camp may serve as a blueprint for other similar programs across the nation with the goal of addressing the URM pipeline in neuroscience.