1. Lee CYQ, Balasuriya GK, Herath M, Franks AE, Hill-Yardin EL. Impaired cecal motility and secretion alongside expansion of gut-associated lymphoid tissue in the Nlgn3(R451C) mouse model of autism. Sci Rep;2023 (Aug 4);13(1):12687.

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.

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2. Leung BK, Merlin S, Walker AK, Lawther AJ, Paxinos G, Eapen V, Clarke R, Balleine BW, Furlong TM. Immp2l knockdown in male mice increases stimulus-driven instrumental behaviour but does not alter goal-directed learning or neuron density in cortico-striatal circuits in a model of Tourette syndrome and autism spectrum disorder. Behav Brain Res;2023 (Aug 24);452:114610.

Cortico-striatal neurocircuits mediate goal-directed and habitual actions which are necessary for adaptive behaviour. It has recently been proposed that some of the core symptoms of autism spectrum disorder (ASD) and Gilles de la Tourette syndrome (GTS), such as tics and other repetitive behaviours, may emerge because of imbalances in these neurocircuits. We have recently developed a model of ASD and GTS by knocking down Immp2l, a mitochondrial gene frequently associated with these disorders. The current study sought to determine whether Immp2l knockdown (KD) in male mice alters flexible, goal- or cue- driven behaviour using procedures specifically designed to examine response-outcome and stimulus-response associations, which underlie goal-directed and habitual behaviour, respectively. Whether Immp2l KD alters neuron density in cortico-striatal neurocircuits known to regulate these behaviours was also examined. Immp2l KD mice and wild type-like mice (WT) were trained on Pavlovian and instrumental learning procedures where auditory cues predicted food delivery and lever-press responses earned a food outcome. It was demonstrated that goal-directed learning was not changed for Immp2l KD mice compared to WT mice, as lever-press responses were sensitive to changes in the value of the food outcome, and to contingency reversal and degradation. There was also no difference in the capacity of KD mice to form habitual behaviours compared to WT mice following extending training of the instrumental action. However, Immp2l KD mice were more responsive to auditory stimuli paired with food as indicated by a non-specific increase in lever response rates during Pavlovian-to-instrumental transfer. Finally, there were no alterations to neuron density in striatum or any prefrontal cortex or limbic brain structures examined. Thus, the current study suggests that Immp2l is not necessary for learned maladaptive goal or stimulus driven behaviours in ASD or GTS, but that it may contribute to increased capacity for external stimuli to drive behaviour. Alterations to stimulus-driven behaviour could potentially influence the expression of tics and repetitive behaviours, suggesting that genetic alterations to Immp2l may contribute to these core symptoms in ASD and GTS. Given that this is the first application of this battery of instrumental learning procedures to a mouse model of ASD or GTS, it is an important initial step in determining the contribution of known risk-genes to goal-directed versus habitual behaviours, which should be more broadly applied to other rodent models of ASD and GTS in the future.

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3. Lewis S, Woroch A, Hatch MK, Lozano R. Autosomal Recessive Limb-Girdle Muscular Dystrophy-3: A Case Report of a Patient with Autism Spectrum Disorder. Genes (Basel);2023 (Aug 5);14(8)

Limb-girdle muscular dystrophies are a group of genetic disorders classically manifesting with progressive proximal muscle weakness. Affected individuals present with atrophy and weakness of the muscles of the shoulders and hips, and in some cases, intellectual disability or developmental delay has also been reported. Limb-girdle muscular dystrophy-3 is a recessive disorder caused by biallelic variants in the SGCA gene. Similarly, symptoms include proximal muscle weakness, elevated CPK, calf muscle pseudohypertrophy, and mobility issues. Cardiac symptoms and respiratory insufficiency are also common symptoms. This case report details a 3-year-old male with muscular weakness, elevated CK, and a neurodevelopmental disorder in whom a homozygous missense variant in c.229C>T (p.Arg77Cys) associated with limb-girdle muscular dystrophy-3 was found. This report shows the association between SGCA c.229C>T and neurodevelopmental disorders as observed in other muscular dystrophies.

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4. Ruggiero-Ruff RE, Villa PA, Hijleh SA, Avalos B, DiPatrizio NV, Haga-Yamanaka S, Coss D. Increased body weight in mice with fragile X messenger ribonucleoprotein 1 (Fmr1) gene mutation is associated with hypothalamic dysfunction. Sci Rep;2023 (Aug 4);13(1):12666.

Mutations in the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene are linked to Fragile X Syndrome, the most common monogenic cause of intellectual disability and autism. People affected with mutations in FMR1 have higher incidence of obesity, but the mechanisms are largely unknown. In the current study, we determined that male Fmr1 knockout mice (KO, Fmr1(-/y)), but not female Fmr1(-/-), exhibit increased weight when compared to wild-type controls, similarly to humans with FMR1 mutations. No differences in food or water intake were found between groups; however, male Fmr1(-/y) display lower locomotor activity, especially during their active phase. Moreover, Fmr1(-/y) have olfactory dysfunction determined by buried food test, although they exhibit increased compulsive behavior, determined by marble burying test. Since olfactory brain regions communicate with hypothalamic regions that regulate food intake, including POMC neurons that also regulate locomotion, we examined POMC neuron innervation and numbers in Fmr1(-/y) mice. POMC neurons express Fmrp, and POMC neurons in Fmr1(-/y) have higher inhibitory GABAergic synaptic inputs. Consistent with increased inhibitory innervation, POMC neurons in the Fmr1(-/y) mice exhibit lower activity, based on cFOS expression. Notably, Fmr1(-/y) mice have fewer POMC neurons than controls, specifically in the rostral arcuate nucleus, which could contribute to decreased locomotion and increased body weight. These results suggest a role for Fmr1 in the regulation of POMC neuron function and the etiology of Fmr1-linked obesity.

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5. Shahin K, Soleimani-Delfan A, He Z, Sansonetti P, Collard JM. Metagenomics revealed a correlation of gut phageome with autism spectrum disorder. Gut Pathog;2023 (Aug 4);15(1):39.

The human gut bacteriome is believed to have pivotal influences on human health and disease while the particular roles associated with the gut phageome have not been fully characterized yet with few exceptions. It is argued that gut microbiota can have a potential role in autism spectrum disorders (ASD). The public microbiota database of ASD and typically developing (TD) Chinese individuals were analyzed for phage protein-coding units (pPCU) to find any link between the phageome and ASD. The gut phageome of ASD individuals showed a wider diversity and higher abundance compared to TD individuals. The ASD phageome was associated with a significant expansion of Caudoviricetes bacteriophages. Phages infecting Bacteroidaceae and prophages encoded within Faecalibacterium were more frequent in ASD than in TD individuals. The expansion and diversification of ASD phageome can influence the bacterial homeostasis by imposing pressure on the bacterial communities. In conclusion, the differences of phages community in in ASD and TD can be used as potential diagnosis biomarkers of ASD. Further investigations are needed to verify the role of gut phage communities in the pathogenesis of ASD.

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6. Sheth F, Shah J, Jain D, Shah S, Patel H, Patel K, Solanki DI, Iyer AS, Menghani B, Mhatre P, Mehta S, Bajaj S, Patel V, Pandya M, Dhami D, Patel D, Sheth J, Sheth H. Comparative yield of molecular diagnostic algorithms for autism spectrum disorder diagnosis in India: evidence supporting whole exome sequencing as first tier test. BMC Neurol;2023 (Aug 5);23(1):292.

BACKGROUND: Autism spectrum disorder (ASD) affects 1 in 100 children globally with a rapidly increasing prevalence. To the best of our knowledge, no data exists on the genetic architecture of ASD in India. This study aimed to identify the genetic architecture of ASD in India and to assess the use of whole exome sequencing (WES) as a first-tier test instead of chromosomal microarray (CMA) for genetic diagnosis. METHODS: Between 2020 and 2022, 101 patient-parent trios of Indian origin diagnosed with ASD according to the Diagnostic and Statistical Manual, 5th edition, were recruited. All probands underwent a sequential genetic testing pathway consisting of karyotyping, Fragile-X testing (in male probands only), CMA and WES. Candidate variant validation and parental segregation analysis was performed using orthogonal methods. RESULTS: Of 101 trios, no probands were identified with a gross chromosomal anomaly or Fragile-X. Three (2.9%) and 30 (29.7%) trios received a confirmed genetic diagnosis from CMA and WES, respectively. Amongst diagnosis from WES, SNVs were detected in 27 cases (90%) and CNVs in 3 cases (10%), including the 3 CNVs detected from CMA. Segregation analysis showed 66.6% (n = 3 for CNVs and n = 17 for SNVs) and 16.6% (n = 5) of the cases had de novo and recessive variants respectively, which is in concordance with the distribution of variant types and mode of inheritance observed in ASD patients of non-Hispanic white/ European ethnicity. MECP2 gene was the most recurrently mutated gene (n = 6; 20%) in the present cohort. Majority of the affected genes identified in the study cohort are involved in synaptic formation, transcription and its regulation, ubiquitination and chromatin remodeling. CONCLUSIONS: Our study suggests de novo variants as a major cause of ASD in the Indian population, with Rett syndrome as the most commonly detected disorder. Furthermore, we provide evidence of a significant difference in the diagnostic yield between CMA (3%) and WES (30%) which supports the implementation of WES as a first-tier test for genetic diagnosis of ASD in India.

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7. Zavaleta-Ramírez P, Rosetti M, Albores-Gallo L, López ON, González PP. Pediatric and psychiatric models of autism care in Mexico: Differences in diagnostic tools and prescribed interventions. Clin Child Psychol Psychiatry;2023 (Aug 4):13591045231193817.

Low- and middle-income countries face heterogeneity in the way clinicians’ approach Autism Spectrum Disorder (ASD) diagnosis and treatment. The current study analyzes the diagnostic tools, laboratory tests, pharmacological and psychosocial interventions received by patients during the steps to diagnosis and treatment of two specialized care centers. Researchers interviewed families with a child with ASD receiving services at either a child psychiatric or a pediatric hospital. Of the total sample, 47% reported clinicians not using a diagnostic tool, 20% reported not receiving any psychosocial intervention, and 88% reported receiving a pharmacological prescription. Patients at the pediatric hospital were more likely to receive interventions with some components of Applied Behavioral Analysis, Early Start Denver Model, Treatment and Education of Autistic and Related Communication Handicapped Children, and Sensory integration therapy; while patients at the psychiatric hospital were more likely to undergo learning, daily living skills, and socialization therapies. Patients at the psychiatric hospital received significantly more requests to obtain auditory and vision tests whilst genetic testing and imaging were more common in the pediatric hospital. The range and variability in terms of diagnostic tools, laboratory tests, and treatment options observed for both sites reflect a lack of consensus. Recommendations to improve ASD diagnostic and treatment in Mexico are given.

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8. Zhao P, Chen X, Bellafard A, Murugesan A, Quan J, Aharoni D, Golshani P. Accelerated social representational drift in the nucleus accumbens in a model of autism. bioRxiv;2023 (Aug 5)

Impaired social interaction is one of the core deficits of autism spectrum disorder (ASD) and may result from social interactions being less rewarding. How the nucleus accumbens (NAc), as a key hub of reward circuitry, encodes social interaction and whether these representations are altered in ASD remain poorly understood. We identified NAc ensembles encoding social interactions by calcium imaging using miniaturized microscopy. NAc population activity, specifically D1 receptor-expressing medium spiny neurons (D1-MSNs) activity, predicted social interaction epochs. Despite a high turnover of NAc neurons modulated by social interaction, we found a stable population code for social interaction in NAc which was dramatically degraded in Cntnap2 (-/-) mouse model of ASD. Surprisingly, non-specific optogenetic inhibition of NAc core neurons increased social interaction time and significantly improved sociability in Cntnap2 (-/-) mice. Inhibition of D1- or D2-MSNs showed reciprocal effects, with D1 inhibition decreasing social interaction and D2 inhibition increasing interaction. Therefore, social interactions are preferentially, specifically and dynamically encoded by NAc neurons and social representations are degraded in this autism model.

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