Herath M

References (3)

Title : Quantitative Spatial Analysis of Neuroligin-3 mRNA Expression in the Enteric Nervous System Reveals a Potential Role in Neuronal-Glial Synapses and Reduced Expression in Nlgn3(R451C) Mice - Herath_2023_Biomolecules_13_
Author(s) : Herath M , Cho E , Marklund U , Franks AE , Bornstein JC , Hill-Yardin EL
Ref : Biomolecules , 13 : , 2023
Abstract : Mutations in the Neuroligin-3 (Nlgn3) gene are implicated in autism spectrum disorder (ASD) and gastrointestinal (GI) dysfunction, but cellular Nlgn3 expression in the enteric nervous system remains to be characterised. We combined RNAScope in situ hybridization and immunofluorescence to measure Nlgn3 mRNA expression in cholinergic and VIP-expressing submucosal neurons, nitrergic and calretinin-containing myenteric neurons and glial cells in both WT and Nlgn3(R451C) mutant mice. We measured Nlgn3 mRNA neuronal and glial expression via quantitative three-dimensional image analysis. To validate dual RNAScope/immunofluorescence data, we interrogated available single-cell RNA sequencing (scRNASeq) data to assess for Nlgn3, Nlgn1, Nlgn2 and their binding partners, Nrxn1-3, MGDA1 and MGDA2, in enteric neural subsets. Most submucosal and myenteric neurons expressed Nlgn3 mRNA. In contrast to other Nlgns and binding partners, Nlgn3 was strongly expressed in enteric glia, suggesting a role for neuroligin-3 in mediating enteric neuron-glia interactions. The autism-associated R451C mutation reduces Nlgn3 mRNA expression in cholinergic but not in VIPergic submucosal neurons. In the myenteric plexus, Nlgn3 mRNA levels are reduced in calretinin, nNOS-labelled neurons and S100 beta -labelled glia. We provide a comprehensive cellular profile for neuroligin-3 expression in ileal neuronal subpopulations of mice expressing the R451C autism-associated mutation in Nlgn3, which may contribute to the understanding of the pathophysiology of GI dysfunction in ASD.
ESTHER : Herath_2023_Biomolecules_13_
PubMedSearch : Herath_2023_Biomolecules_13_
PubMedID: 37509099

Title : Impaired cecal motility and secretion alongside expansion of gut-associated lymphoid tissue in the Nlgn3(R451C) mouse model of autism - Lee_2023_Sci.Rep_13_12687
Author(s) : Lee CYQ , Balasuriya GK , Herath M , Franks AE , Hill-Yardin EL
Ref : Sci Rep , 13 :12687 , 2023
Abstract : Individuals with Autism Spectrum Disorder (ASD; autism) commonly present with gastrointestinal (GI) illness in addition to core diagnostic behavioural traits. The appendix, or cecum in mice, is important for GI homeostasis via its function as a key site for fermentation and a microbial reservoir. Even so, the role of the appendix and cecum in autism-associated GI symptoms remains uninvestigated. Here, we studied mice with an autism-associated missense mutation in the post-synaptic protein neuroligin-3 (Nlgn3(R451C)), which impacts brain and enteric neuronal activity. We assessed for changes in cecal motility using a tri-cannulation video-imaging approach in ex vivo preparations from wild-type and Nlgn3(R451C) mice. We investigated cecal permeability and neurally-evoked secretion in wild-type and Nlgn3(R451C) tissues using an Ussing chamber set-up. The number of cecal patches in fresh tissue samples were assessed and key immune populations including gut macrophages and dendritic cells were visualised using immunofluorescence. Nlgn3(R451C) mice displayed accelerated cecal motor complexes and reduced cecal weight in comparison to wildtype littermates. Nlgn3(R451C) mice also demonstrated reduced neurally-evoked cecal secretion in response to the nicotinic acetylcholine receptor agonist 1,1-dimethyl-4-phenylpiperazinium (DMPP), but permeability was unchanged. We observed an increase in the number of cecal patches in Nlgn3(R451C) mice, however the cellular morphologies of key immune populations studied were not significantly altered. We show that the R451C nervous system mutation leads to cecal dysmotility, impaired secretion, and neuro-immune alterations. Together, these results suggest that the R451C mutation disrupts the gut-brain axis with GI dysfunction in autism.
ESTHER : Lee_2023_Sci.Rep_13_12687
PubMedSearch : Lee_2023_Sci.Rep_13_12687
PubMedID: 37542090
Gene_locus related to this paper: mouse-3neur

Title : The Emerging Role of the Gut-Brain-Microbiota Axis in Neurodevelopmental Disorders - Hosie_2022_Adv.Exp.Med.Biol_1383_141
Author(s) : Hosie S , Abo-Shaban T , Lee CYQ , Matta SM , Shindler A , Gore R , Sharna SS , Herath M , Crack PJ , Franks AE , Hill-Yardin EL
Ref : Advances in Experimental Medicine & Biology , 1383 :141 , 2022
Abstract : Autism spectrum disorder (ASD; autism) is a prevalent neurodevelopmental disorder associated with changes in gut-brain axis communication. Gastrointestinal (GI) symptoms are experienced by a large proportion of individuals diagnosed with autism. Several mutations associated with autism modify cellular communication via neuronal synapses. It has been suggested that modifications to the enteric nervous system, an intrinsic nervous system of the GI tract, could contribute to GI dysfunction. Changes in gut motility, permeability, and the mucosal barrier as well as shifts in the large population of microbes inhabiting the GI tract could contribute to GI symptoms. Preclinical research has demonstrated that mice expressing the well-studied R451C missense mutation in Nlgn3 gene, which encodes cell adhesion protein neuroligin-3 at neuronal synapses, exhibit GI dysfunction. Specifically, NL3(R451C) mice show altered colonic motility and faster small intestinal transit. As well as dysmotility, macrophages located within the gut-associated lymphoid tissue of the NL3(R451C) mouse caecum show altered morphology, suggesting that neuro-inflammation pathways are modified in this model. Interestingly, NL3(R451C) mice maintained in a shared environment demonstrate fecal microbial dysbiosis indicating a role for the nervous system in regulating gut microbial populations. To better understand host-microbe interactions, further clarification and comparison of clinical and animal model profiles of dysbiosis should be obtained, which in turn will provide better insights into the efforts taken to design personalized microbial therapies. In addition to changes in neurophysiological measures, the mucosal component of the GI barrier may contribute to GI dysfunction more broadly in individuals diagnosed with a wide range of neurological disorders. As the study of GI dysfunction advances to encompass multiple components of the gut-brain-microbiota axis, findings will help understand future directions such as microbiome engineering and optimisation of the mucosal barrier for health.
ESTHER : Hosie_2022_Adv.Exp.Med.Biol_1383_141
PubMedSearch : Hosie_2022_Adv.Exp.Med.Biol_1383_141
PubMedID: 36587154
Gene_locus related to this paper: human-NLGN3