Gastrointestinal dysfunction in patients and mice expressing the autism‐associated R451C mutation in neuroligin‐3 (original) (raw)
Related papers
Colonic dilation and altered ex vivo gastrointestinal motility in the neuroligin‐3 knockout mouse
Autism Research
Gastrointestinal (GI) dysfunction is commonly reported by people diagnosed with autism spectrum disorder (ASD; autism) but the cause is unknown. Mutations in genes encoding synaptic proteins including Neuroligin-3 are associated with autism. Mice lacking Neuroligin-3 (Nlgn3 −/−) have altered brain function, but whether the enteric nervous system (ENS) is altered remains unknown. We assessed for changes in GI structure and function in Nlgn3 −/− mice. We found no significant morphological differences in villus height or crypt depth in the jejunum or colon between wildtype (WT) and Nlgn3 −/− mice. To determine whether deletion of Nlgn3 affects enteric neurons, we stained for neural markers in the myenteric plexus. Nlgn3 −/− mice had similar numbers of neurons expressing the pan-neuronal marker Hu in the jejunum, proximal mid, and distal colon regions. We also found no differences in the number of neuronal nitric oxide synthase (nNOS+) or calretinin (CalR+) motor neurons and interneurons between WT and Nlgn3 −/− mice. We used ex vivo video imaging analysis to assess colonic motility under baseline conditions and observed faster colonic migrating motor complexes (CMMCs) and an increased colonic diameter in Nlgn3 −/− mice, although CMMC frequency was unchanged. At baseline, CMMCs were faster in Nlgn3 −/− mice compared to WT. Although the numbers of neuronal subsets are conserved in Nlgn3 −/− mice, these findings suggest that Neuroligin-3 modulates inhibitory neural pathways in the ENS and may contribute to mechanisms underlying GI disorders in autism. Autism Res 2019, 00: 1-11.
Colonic dilation and altered ex vivo gastrointestinal motility in the neuroligin‐3 knockout mouse
Autism Research, 2019
Gastrointestinal (GI) dysfunction is commonly reported by people diagnosed with autism spectrum disorder (ASD; autism) but the cause is unknown. Mutations in genes encoding synaptic proteins including Neuroligin-3 are associated with autism. Mice lacking Neuroligin-3 (Nlgn3 −/−) have altered brain function, but whether the enteric nervous system (ENS) is altered remains unknown. We assessed for changes in GI structure and function in Nlgn3 −/− mice. We found no significant morphological differences in villus height or crypt depth in the jejunum or colon between wildtype (WT) and Nlgn3 −/− mice. To determine whether deletion of Nlgn3 affects enteric neurons, we stained for neural markers in the myenteric plexus. Nlgn3 −/− mice had similar numbers of neurons expressing the pan-neuronal marker Hu in the jejunum, proximal mid, and distal colon regions. We also found no differences in the number of neuronal nitric oxide synthase (nNOS+) or calretinin (CalR+) motor neurons and interneurons between WT and Nlgn3 −/− mice. We used ex vivo video imaging analysis to assess colonic motility under baseline conditions and observed faster colonic migrating motor complexes (CMMCs) and an increased colonic diameter in Nlgn3 −/− mice, although CMMC frequency was unchanged. At baseline, CMMCs were faster in Nlgn3 −/− mice compared to WT. Although the numbers of neuronal subsets are conserved in Nlgn3 −/− mice, these findings suggest that Neuroligin-3 modulates inhibitory neural pathways in the ENS and may contribute to mechanisms underlying GI disorders in autism. Autism Res 2019, 00: 1-11.
ABSTRACTMutations in the Neuroligin-3 (Nlgn3) gene are implicated in autism spectrum disorder (ASD) and gastrointestinal (GI) dysfunction but its cellular expression in the GI tract remains to be characterised. Localisation of NLGN3 protein is challenging in intestinal tissue due to the lack of target-specific antibodies. Here, we combined RNAScopein situhybridization forNlgn3mRNA and immunofluorescence for markers of all enteric neurons, cholinergic submucosal neurons, non-cholinergic submucosal neurons, nitregic and calretinin-containing myenteric neurons as well as glial cells. We also developed a quantitative 3-dimensional image analysis method to measureNlgn3mRNA cellular expression levels in enteric neurons and glia. We show thatNlgn3mRNA is expressed in most submucosal and myenteric neurons as well as in enteric glia. The R451C mutation reducesNlgn3mRNA expression levels in cholinergic, nitrergic and calretinin enteric neuronal subpopulations but does not affectNlgn3mRNA expr...
Preventive Medicine, 2011
Autism spectrum disorders (ASDs) are pervasive neurodevelopmental disorders, characterized by impairments in social interaction and communication and the presence of limited, repetitive and stereotyped interests and behavior. Bowel symptoms are frequently reported in children with ASD and a potential role for gastrointestinal disturbances in ASD has been suggested. This review focuses on the importance of (allergic) gastrointestinal problems in ASD. We provide an overview of the possible gut-to-brain pathways and discuss opportunities for pharmaceutical and/or nutritional approaches for therapy.
F1000 - Post-publication peer review of the biomedical literature, 2007
Autism spectrum disorders (ASDs) are characterized by impairments in social behaviors that are sometimes coupled to specialized cognitive abilities. A small percentage of ASD patients carry mutations in genes encoding neuroligins, which are postsynaptic cell adhesion molecules. Here we introduce one of these mutations into mice-the R451C-substitution in neuroligin-3. R451Cmutant mice showed impaired social interactions but enhanced spatial learning abilities. Unexpectedly, these behavioral changes were accompanied by an increase in inhibitory synaptic transmission, with no apparent effect on excitatory synapses. Deletion of neuroligin-3, in contrast, did not cause such changes, indicating that the R451C-substitution represents a gain-of-function mutation. These data suggest that increased inhibitory synaptic transmission may contribute to human ASDs and that the R451C KI mice may be a useful model for studying autism-related behaviors. Autism is a widespread cognitive disorder characterized by impairments in social interactions, including verbal communication and social play, and can be accompanied by stereotyped patterns of behavior (1-3). Autism is a heterogeneous condition, prompting the designation of "autism spectrum disorders" (ASDs). Individuals with ASDs occasionally show enhanced cognitive abilities (the 'autistic savant syndrome' [4]). At the other end of the spectrum, ASDs are often associated with mental retardation, and the symptoms of ASDs are part of several neurological diseases, such as fragile X-and Rett-syndrome (5-7). Genetics strongly contributes to ASDs (1,2), and a small number of cases with idiopathic ASD are associated with mutations in a single gene, including genes encoding neuroligins and their associated proteins (8).
The Journal of Neuroscience, 2020
Neuroligins (NLGNs) are a class of postsynaptic cell adhesion molecules that interact with presynaptic neurexins (NRXNs) and regulate synapse function. NLGN4 is a member of the NLGN family and consists of a unique amino acid sequence in humans that is not evolutionarily well conserved in rodents. The human-specific NLGN4 gene has been reported to be mutated in many patients with autism and other neurodevelopmental disorders. However, it remained unclear how these mutations might alter the molecular properties of NLGN4 and affect synaptic transmission in human neurons. Here, we describe a severely autistic male patient carrying a single amino acid substitution (R101Q) in the NLGN4 gene. When expressed in HEK293 cells, the R101Q mutation in NLGN4 did not affect its binding affinity for NRXNs or its capacity to form homodimers. This mutation, however, impaired the maturation of NLGN4 protein by inhibiting N-linked glycosylation at an adjacent residue (N102), which is conserved in all NLGNs. As a result, the R101Q substitution significantly decreased the surface trafficking of NLGN4 and increased its retention in the endoplasmic reticulum and Golgi apparatus. In human neurons derived from male stem cell lines, the R101Q mutation also similarly reduced the synaptic localization of NLGN4, resulting in a loss-of-function phenotype. This mutation-induced trafficking defect substantially diminished the ability of NLGN4 to form excitatory synapses and modulate their functional properties. Viewed together, our findings suggest that the R101Q mutation is pathogenic for NLGN4 and can lead to synaptic dysfunction in autism.
Proceedings of the National Academy of Sciences of the United States of America, 2011
Multiple independent mutations in neuroligin genes were identified in patients with familial autism, including the R451C substitution in neuroligin-3 (NL3). Previous studies showed that NL3(R451C) knock-in mice exhibited modestly impaired social behaviors, enhanced water maze learning abilities, and increased synaptic inhibition in the somatosensory cortex, and they suggested that the behavioral changes in these mice may be caused by a general shift of synaptic transmission to inhibition. Here, we confirm that NL3(R451C) mutant mice behaviorally exhibit social interaction deficits and electrophysiologically display increased synaptic inhibition in the somatosensory cortex. Unexpectedly, however, we find that the NL3(R451C) mutation produced a strikingly different phenotype in the hippocampus. Specifically, in the hippocampal CA1 region, the NL3(R451C) mutation caused an ∼1.5-fold increase in AMPA receptor-mediated excitatory synaptic transmission, dramatically altered the kinetics o...
Physiological reports, 2014
Neuroligins are postsynaptic adhesion molecules that interacting with presynaptic neurexins ensure the cross-talk between pre- and postsynaptic specializations. Rare mutations in neurexin-neuroligin genes have been linked to autism spectrum disorders (ASDs). One of these, the R451C mutation of the gene encoding for Neuroligin3 (Nlgn3), has been found in patients with familial forms of ASDs. Animals carrying this mutation (NL3(R451C) knock-in mice) exhibit impaired social behaviors, reminiscent of those observed in ASD patients, associated with major alterations in both GABAergic and glutamatergic transmission, which vary among different brain regions and at different developmental stages. Here, pair recordings from parvalbumin- (PV) expressing basket cells and spiny neurons were used to study GABAergic synaptic signaling in layer IV barrel cortex of NL3(R451C) mutant mice. We found that the R451C mutation severely affects the probability of GABA release from PV-expressing basket cel...