Gastrointestinal (GI) problems constitute an important comorbidity in many patients with autism. Multiple mutations in the neuroligin family of synaptic adhesion molecules are implicated in autism, however whether they are expressed and impact GI function via changes in the enteric nervous system is unknown. We report the GI symptoms of two brothers with autism and an R451C mutation in Nlgn3 encoding the synaptic adhesion protein, neuroligin‐3. We confirm the presence of an array of synaptic genes in the murine GI tract and investigate the impact of impaired synaptic protein expression in mice carrying the human neuroligin‐3 R451C missense mutation (NL3 R451C ). Assessing in vivo gut dysfunction, we report faster small intestinal transit in NL3 R451C compared to wild‐type mice. Using an ex vivo colonic motility assay, we show increased sensitivity to GABA A receptor modulation in NL3 R451C mice, a well‐established Central Nervous System (CNS) feature associated with this mutation. We further show increased numbers of small intestine myenteric neurons in NL3 R451C mice. Although we observed altered sensitivity to GABA A receptor modulators in the colon, there was no change in colonic neuronal numbers including the number of GABA‐immunoreactive myenteric neurons. We further identified altered fecal microbial communities in NL3 R451C mice. These results suggest that the R451C mutation affects small intestinal and colonic function and alter neuronal numbers in the small intestine as well as impact fecal microbes. Our findings identify a novel GI phenotype associated with the R451C mutation and highlight NL3 R451C mice as a useful preclinical model of GI dysfunction in autism. Autism Res 2019, 12: 1043–1056 . © 2019 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary People with autism commonly experience gastrointestinal problems, however the cause is unknown. We report gut symptoms in patients with the autism‐associated R451C mutation encoding the neuroligin‐3 protein. We show that many of the genes implicated in autism are expressed in mouse gut. The neuroligin‐3 R451C mutation alters the enteric nervous system, causes gastrointestinal dysfunction, and disrupts gut microbe populations in mice. Gut dysfunction in autism could be due to mutations that affect neuronal communication.

Recent studies demonstrate a differential trajectory for cannabinoid receptor expression in cortical and sub-cortical brain areas across postnatal development. In the present study, we sought to investigate whether chronic systemic exposure to a synthetic cannabinoid receptor agonist causes morphological changes in the structure of dendrites and dendritic spines in adolescent and adult pyramidal neurons in the medial prefrontal cortex (mPFC) and medium spiny neurons (MSN) in the nucleus accumbens (Acb). Following systemic administration of WIN 55,212-2 in adolescent (PN 37–40) and adult (P55–60) male rats, the neuronal architecture of pyramidal neurons and MSN was assessed using Golgi–Cox staining. While no structural changes were observed in WIN 55,212-2-treated adolescent subjects compared to control, exposure to WIN 55,212-2 significantly increased dendritic length, spine density and the number of dendritic branches in pyramidal neurons in the mPFC of adult subjects when compared to control and adolescent subjects. In the Acb, WIN 55,212-2 exposure significantly decreased dendritic length and number of branches in adult rat subjects while no changes were observed in the adolescent groups. In contrast, spine density was significantly decreased in both the adult and adolescent groups in the Acb. To determine whether regional developmental morphological changes translated into behavioral differences, WIN 55,212-2-induced aversion was evaluated in both groups using a conditioned place preference paradigm. In adult rats, WIN 55,212-2 administration readily induced conditioned place aversion as previously described. In contrast, adolescent rats did not exhibit aversion following WIN 55,212-2 exposure in the behavioral paradigm. The present results show that synthetic cannabinoid administration differentially impacts cortical and sub-cortical neuronal morphology in adult compared to adolescent subjects. Such differences may underlie the disparate development effects of cannabinoids on behavior.

Antenatal treatment with synthetic glucocorticoids is commonly used in pregnant women at risk of preterm delivery to accelerate tissue maturation. Exposure to glucocorticoids during development has been hypothesized to underlie different functional gastrointestinal (GI) and motility disorders. Herein, we investigated the impact of in utero exposure to synthetic glucocorticoids (iuGC) on GI function of adult rats. Wistar male rats, born from pregnant dams treated with dexamethasone (DEX), were studied at different ages. Length, histologic analysis, proliferation and apoptosis assays, GI transit, permeability and serotonin (5-HT) content of GI tract were measured. iuGC treatment decreased small intestine size and decreased gut transit. However, iuGC had no impact on intestinal permeability. iuGC differentially impacts the structure and function of the GI tract, which leads to long-lasting alterations in the small intestine that may predispose subjects prone to disorders of the GI tract.

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