Biology subjects

Osman, A.

Publications and source records attributed to Osman, A..

17 recordsLinked to original sources

bioRxiv2026

Ketamine Modulates Endogenous Opioid Peptide Signaling and Reduces Heroin-Seeking in Male Long-Evans Rats

Opioid Use Disorder (OUD) continues to be a pressing public health crisis, marked by high relapse rates and limited treatment options. Ketamine, a non-competitive N-Methyl-D-Aspartate receptor (NMDAR) antagonist, has emerged as a promising therapeutic for numerous psychiatric illnesses due to its robust antidepressant properties and glutamate-mediated synaptic plasticity. However, ketamine's therapeutic mechanisms remain elusive, with emerging evidence implicating the endogenous opioid system. Furthermore, few studies have investigated ketamine's potential as an intervention for OUD. Accordingly, this study assessed ketamine's ability to rewire endogenous opioid and glutamatergic circuitry and reduce heroin-seeking activity in male Long-Evans rats. Using a multi-cohort design, we investigated ketamine's effects on opioid-related transcriptional, protein, and signaling properties in key brain regions associated with reward and addiction, and subsequently on heroin-seeking using a self-administration paradigm. To investigate mechanisms of plasticity, we also quantified transcriptional changes to NMDAR subunits. Molecular analyses demonstrated increased expression of endogenous opioid system-related genes and endogenous opioid peptides at the protein level, elevated mu-opioid receptor protein levels, and enhanced G protein activity, suggesting increased receptor function. Notably, transcriptional changes were particularly prominent in the shell subregion of the nucleus accumbens (NAc). We also revealed that ketamine altered NMDAR subunit expression in the medial prefrontal cortex and NAc, indicating circuit-level synaptic remodeling. Behavioral analyses revealed that ketamine significantly reduced heroin-primed, but not cue-induced, seeking activity. Together, these findings suggest ketamine reduces acute relapse vulnerability to opioids through coordinated modulation of opioid and glutamatergic systems, highlighting its potential as a novel intervention for OUD.

neuroscience↗

bioRxiv2026

How Phosphorylation of How Phosphorylation of alpha/beta-Tubulin Perturbs Microtubule Structure: A Computational Study

Microtubules are cytoskeletal structures composed of polymers of /{beta}-tubulin heterodimers that enable cell division and motility by a process of alternating episodes of polymerization and depolymerization (dynamic instability). Transition from a polymerizing to a depolymerizing microtubule is triggered at the interdimer interface by Glu254 in -tubulin (:Glu254), which hydrolyzes GTP bound to {beta}-tubulin ({beta}:GTP). The process is regulated by phosphorylation of -tubulin (Ser165) or {beta}-tubulin (Ser172) via signaling protein kinases (PKC, CDK1). All-atom molecular dynamics simulations of /{beta}-tubulin 6-mer systems are used to screen the cryo-EM structure of a microtubule (PDB 3J6E) for structural responses to phosphorylation of each tubulin subunit. In terms of global structure, microtubules with phosphorylated -tubulin have a straight conformation attributed to a growing microtubule, whereas MTs with phosphorylated {beta}-tubulin are curved, characteristic of a disassembling MT. Phospho--tubulin initiates displacement of key secondary structures (helix H8, loop T5) at the inter-dimer interface, shifts the {beta}:GTP nucleotide by 5 [A], and immobilizes the {gamma}-phosphate of {beta}:GTP through increased H-bonding with {beta}-tubulin. Phospho-{beta}-tubulin produces fewer structural effects and has a more flexible {beta}:GTP. For {beta}:GTP hydrolysis, the phospho-{beta}-tubulin system displays an extensive network of water molecules between :Glu254 and the {gamma}-phosphate of {beta}:GTP, facilitating its hydrolysis. In contrast, phospho--tubulin displays a discontinuous network of water molecules that predicts a diminished capacity for {beta}:GTP hydrolysis. These findings provide a detailed framework for understanding how phosphorylation of each tubulin subunit restructures the inter-dimer interface to modulate {beta}:GTP hydrolysis, global structure, and dynamic instability in response to key signaling protein kinases.

biochemistry↗

bioRxiv2026

A human synovial tendon-on-a-chip models key features of peritendinous adhesions and offers a new approach methodology for testing anti-fibrotic drugs

Peritendinous adhesions are a debilitating complication of tendon injury characterized by excessive matrix deposition and chronic inflammation. Due to limitations of current preclinical models, the underlying mechanisms of adhesion pathogenesis remain poorly defined, and there are no approved drugs to prevent or resolve adhesions. Here, we develop a human synovial tendon-on-a-chip (synToC) that integrates synovial fibroblasts, tendon-resident fibroblasts, immune cells, and vascular endothelium to reconstruct the intrasynovial tendon microenvironment. We show that synovial fibroblast activation promoted tendon contraction and inflammatory cytokine secretion dominated by IL-6, leading to monocyte infiltration and formation of fibronectin- and collagen III-rich matrix bridges between tendon and synovial compartments resembling nascent peritendinous adhesions. These phenotypes emerged even in the absence of exogenous TGF-{beta}1, indicating that synovial fibroblast-mediated crosstalk is sufficient to initiate adhesion-like pathology. Importantly, pharmacological inhibition of the IL-6/JAK/STAT pathway suppressed synovial activation, blunted inflammatory cytokine signaling, and attenuated fibrotic matrix deposition and interfacial adhesion formation. These findings establish the synToC as a human-relevant new approach methodology (NAM) to interrogate the multicellular drivers of tendon adhesions and to accelerate the development of anti-fibrotic therapies.

bioengineering↗

bioRxiv2026

Granulocyte colony-stimulating factor acts through calcium-permeable AMPA receptors to potentiate cocaine reward

Neuroimmune interactions have emerged as critical modulators of substance use disorders and may represent promising translational therapeutic targets. In prior work, we demonstrated that the cytokine granulocyte colony stimulating factor (G-CSF) is elevated in mice following cocaine exposure, with circulating levels correlating with cocaine intake and locomotor sensitization. Additionally, exogenous G-CSF enhances cocaine reward and increases low-dose cocaine self-administration. We have further shown that repeated G-CSF administration alters expression of glutamatergic synapse-associated proteins following cocaine-seeking behavior. Building on these findings, the present studies examined the molecular consequences of repeated administration of G-CSF, cocaine, or their combination, with a focus on glutamatergic signaling pathways. We also tested whether altered glutamate receptor expression contributes to G-CSF-mediated enhancement of cocaine reward. Repeated combined administration of G-CSF and cocaine produced robust changes in glutamate-associated and synapse-related protein expression within the nucleus accumbens and medial prefrontal cortex. These molecular adaptations were accompanied by increased synaptic density in the nucleus accumbens. Finally, pharmacological inhibition of calcium-permeable AMPA receptors within the nucleus accumbens reversed the G-CSF-induced enhancement of cocaine conditioned place preference. Together, these findings indicate that G-CSF enhances cocaine reward at least in part by promoting glutamatergic synaptic remodeling in the nucleus accumbens, identifying a neuroimmune-glutamate mechanism that may be leveraged for therapeutic intervention.

neuroscience↗

bioRxiv2025

Endothelin-converting enzyme 2 differentially regulates kappa opioid receptor trafficking and function

Following activation by endogenous opioid peptides, mu and delta opioid receptors have been shown to undergo differential internalization and recycling; the rate and extent of recycling but not internalization was found to be regulated by the endocytic peptide converting enzyme, ECE2. This study focuses on kappa opioid receptors (KOR) and the ability of endogenous opioid peptides released by post-translational processing of prodynorphin and proenkephalin to induce KOR and ECE2 internalization/recycling, and how ECE2 modulates these processes. Using a proximity-based ligation assay we show that KOR and ECE2 are in close proximity to facilitate co-internalization. In addition, we find that treatment with longer opioid peptides induces fast and robust internalization and recycling of ECE2 at a rate and extent comparable to that of KOR. Next, we directly examined the role of ECE2 in modulating KOR recycling. We find that ECE2 inhibition significantly attenuates KOR recycling. Finally, we examined the role of ECE2 in modulating KOR signaling and find that resensitization of KOR by peptides that are substrates of ECE2 are attenuated by ECE2 inhibition. Taken with the differential expression of ECE2 in the brain (relatively high expression in midbrain & hypothalamus and low expression in the striatum & hippocampus), these results highlight a pivotal role for ECE2 in differentially modulating KOR function. Significance StatementThis study highlights a role for ECE2 in agonist mediated regulation of KOR function by select prodynorphin and proenkephalin derived peptides. Collectively our studies suggest that ECE2 inhibitors could be developed as therapeutics for pathologies involving dysregulations in KOR signaling.

neuroscience↗

bioRxiv2025

Autocrine CXCL1-CXCR2 Signaling Mediates Leptomeningeal Resistance to Radiation Therapy

Leptomeningeal metastasis (LM) is a fatal neurological complication of cancer. Proton craniospinal irradiation (pCSI) has emerged as a promising life-prolonging intervention for LM patients, but the response to this treatment varies. Here, we aimed to characterize the molecular basis of pCSI resistance and response. Proteomic analysis of CSF collected from LM patients at baseline (before pCSI), and at multiple time points post-treatment, identified the CXC-motif chemokine, CXCL1, as associated with LM growth. Higher CXCL1 levels in the CSF prior to pCSI correlated with worse response to this treatment. To define the role of CXCL1 in LM, we established syngeneic mouse models of LM-CSI. We found that both metastatic cancer and host cells generate CXCL1. Genetic interruption of Cxcl1 expression in metastatic cancer, but not host cells, impaired cancer cell growth within the leptomeninges. Moreover, a subset of LM cancer cells expressed Cxcr2, the primary receptor for Cxcl1, and this population was enriched over time in the leptomeninges. Transcriptomic profiling of this rare population revealed an enrichment in pathways implicated in cell cycle progression. Finally, interruption of Cxcl1-Cxcr2 signaling with intrathecally-delivered Cxcr2 antagonist hampered LM growth and sensitized the cells to CSI. Our results demonstrate that the Cxcl1-Cxcr2 signaling axis mediates LM growth, and identifies a potential actionable intervention to improve response to pCSI and halt LM progression. One Sentence SummaryCXCL1-CXCR2 axis is a potential actionable therapeutic target to halt leptomeningeal metastasis progression and enhance response to craniospinal irradiation.

cancer biology↗

bioRxiv2025

Microglia Adopt Temporally Specific Subtypes after Irradiation, Correlating with Neuronal Asynchrony

Cranial radiotherapy causes progressive neurocognitive impairments in cancer survivors. Neuroinflammation is a key contributor, but its dynamics and consequences for brain function remain poorly understood. Here, we performed comprehensive longitudinal profiling from 6 hours to 1 year after irradiation (IR) of the mouse hippocampus, using transcriptomic, protein, and histological analyses. We identified delayed microglial responses initiated by mitotic progression coupled interferon signaling. IR rewired the parenchymal phagocyte profiles, triggered by progressive microglial loss, failure of repopulation through self-renewal, and compensatory generation of microglia-like cells derived from peripheral monocytes. These findings were also observed in autopsied human brain. Finally, we demonstrate two phases of neuronal asynchrony, an early one associated with inflammation and a late one associated with aberrant synaptic regulation. These results provide comprehensive, longitudinal insights into microglia responses that can aid in tailoring therapies to preserve cognition in cancer survivors.

neuroscience↗

bioRxiv2024

Retinoid X Receptor Signaling Mediates Cancer Cell Lipid Metabolism in the Leptomeninges

Cancer cells metastatic to the leptomeninges encounter a metabolically-challenging extreme microenvironment. To understand adaptations to this space, we subjected leptomeningeal-metastatic (LeptoM) mouse breast and lung cancers isolated from either the leptomeninges or orthotopic primary sites to ATAC-and RNA-sequencing. When inhabiting the leptomeninges, the LeptoM cells demonstrated transcription downstream of retinoid-X-receptors (RXRs). We found evidence of local retinoic acid (RA) generation in both human leptomeningeal metastasis and mouse models in the form of elevated spinal fluid retinol and expression of RA-generating dehydrogenases within the leptomeningeal microenvironment. Stimulating LeptoM cells with RA induced expression of transcripts encoding de novo fatty acid synthesis pathway enzymes in vitro. In vivo, while deletion of Stra6 did not alter cancer cell leptomeningeal growth, knockout of Rxra/b/g interrupted cancer cell lipid biosynthesis and arrested cancer growth. These observations illustrate a mechanism whereby metastatic cancer cells awake locally-generated developmental cues for metabolically reprograming, suggesting novel therapeutic approaches.

cancer biology↗

bioRxiv2024

Intrinsic molecular identifiers enable robust molecular counting in single-cell sequencing

Particle-templated instant partition sequencing (PIPseq), is an emerging approach for massively scalable single-cell gene expression studies that does not require complex instrumentation or expensive consumables. We present PIPseqTM V, a novel implementation of the PIPseq workflow with significant improvements in assay performance and sensitivity compared to prior methods. Among the innovations driving the improved performance in PIPseq V is a new approach for transcript counting using Intrinsic Molecular Identifiers (IMIs) from the captured transcript sequence, eliminating the need for traditional Unique Molecular Identifiers (UMIs). IMIs are the starting positions for molecules generated by random fragmentation after limited cycle PCR, which can be used to uniquely identify individual transcript copies of genes expressed within individual cells. To correct for experimental variation in IMI generation, we have developed a dynamic correction strategy that can adapt to different sample cell input, transcript expression, and sequencing depth without the need for external benchmarking or controls. Our results demonstrate that PIPseq V with IMI-based analysis provides biological information comparable to established UMI-based approaches while avoiding UMI-associated biases. Dynamic correction offers a robust and data-driven analysis strategy for scRNAseq.

genomics↗

bioRxiv2023

Leptomeningeal anti-tumor immunity follows unique signaling principles

Metastasis to the cerebrospinal fluid (CSF)-filled leptomeninges, or leptomeningeal metastasis (LM), represents a fatal complication of cancer. Proteomic and transcriptomic analyses of human CSF reveal a substantial inflammatory infiltrate in LM. We find the solute and immune composition of CSF in the setting of LM changes dramatically, with notable enrichment in IFN-{gamma} signaling. To investigate the mechanistic relationships between immune cell signaling and cancer cells within the leptomeninges, we developed syngeneic lung, breast, and melanoma LM mouse models. Here we show that transgenic host mice, lacking IFN-{gamma} or its receptor, fail to control LM growth. Overexpression of Ifng through a targeted AAV system controls cancer cell growth independent of adaptive immunity. Instead, leptomeningeal IFN-{gamma} actively recruits and activates peripheral myeloid cells, generating a diverse spectrum of dendritic cell subsets. These migratory, CCR7+ dendritic cells orchestrate the influx, proliferation, and cytotoxic action of natural killer cells to control cancer cell growth in the leptomeninges. This work uncovers leptomeningeal-specific IFN-{gamma} signaling and suggests a novel immune-therapeutic approach against tumors within this space.

cancer biology↗

bioRxiv2022

A comprehensive proteomic and bioinformatics analysis of human spinal cord injury plasma identifies proteins associated with the complement cascade and liver function as potential prognostic indicators of neurological outcome

1.1.1. IntroductionSpinal Cord Injury (SCI) is a major cause of disability, with complications post-injury often leading to life-long health issues with need of extensive treatment. Neurological outcome post-SCI can be variable and difficult to predict, particularly in incomplete injured patients. The identification of specific SCI biomarkers in blood, may be able to improve prognostics in the field. This study has utilised proteomic and bioinformatics methodologies to investigate differentially expressed proteins in plasma samples across human SCI cohorts with the aim of identifying prognostic biomarkers and biological pathway alterations that relate to neurological outcome. 1.2. Methods and MaterialsBlood samples were taken, following informed consent, from ASIA impairment scale (AIS) grade C "Improvers" (those who experienced an AIS grade improvement) and "Non-Improvers" (No AIS change), and AIS grade A and D at <2 weeks ("Acute") and approx. 3 months ("Sub-acute") post-injury. The total protein concentration from each sample was extracted, with pooled samples being labelled and non-pooled samples treated with ProteoMiner beads. Samples were then analysed using two 4-plex isobaric tag for relative and absolute quantification (iTRAQ) analyses and a label-free experiment for comparison, before quantifying with mass spectrometry. Data are available via ProteomeXchange with identifiers PXD035025 and PXD035072 for the iTRAQ and label-free experiments respectively. Proteomic datasets were analysed using OpenMS (version 2.6.0). R (version 4.1.4) and in particular, the R packages MSstats (version 4.0.1) and pathview (version 1.32.0) were used for downstream analysis. Proteins of interest identified from this analysis were further validated by enzyme-linked immunosorbent assay (ELISA). 1.3. ResultsThe data demonstrated proteomic differences between the cohorts, with the results from the iTRAQ approach supporting those of the label-free analysis. A total of 79 and 87 differentially abundant proteins across AIS and longitudinal groups were identified from the iTRAQ and label-free analyses, respectively. Alpha-2-macroglobulin (A2M), retinol binding protein 4 (RBP4), serum amyloid A1 (SAA1), Peroxiredoxin 2, Apolipoprotein A1 (ApoA1) and several immunoglobulins were identified as bio-logically relevant and differentially abundant, with potential as individual prognostic biomarkers of neurological outcome. Bioinformatics analyses revealed that the majority of differentially abundant proteins were components of the complement cascade and most interacted directly with the liver. 1.4. ConclusionsMany of the proteins of interest identified using proteomics were detected only in a single group and therefore have potential as a binary (present or absent) biomarkers, RBP4 and PRX-2 in particular. Additional investigations into the chronology of these proteins, and their levels in other tissues (cerebrospinal fluid in particular) are needed to better understand the underlying pathophysiology, including any potentially modifiable targets. Pathway analysis highlighted the complement cascade as being significant across groups of differential functional recovery.

bioinformatics↗

bioRxiv2022

Dietary polyphenols drive alterations in behavior, transcriptional regulation, and commensal microbiota in models of opioid use.

Opioid Use Disorder (OUD) is a neuropsychiatric condition associated with tremendous medical and social consequences. Despite this burden, current pharmacotherapies for OUD are ineffective or intolerable for many patients. As such, interventions aimed at promoting overall health and resilience against OUD are of immense clinical and societal interest. Recently, treatment with a Bioactive Dietary Polyphenol Preparation (BDPP) was shown to promote behavioral resilience and adaptive neuroplasticity in multiple models of neuropsychiatric disease. Here, we assessed effects of BDPP treatment on behavioral and molecular responses to repeated morphine treatment. We find that BDPP pre-treatment alters responses across the dose range for both locomotor sensitization and conditioned place preference. Most notably, polyphenol treatment consistently reduced formation of preference at low dose (5mg/kg) morphine but enhanced it at high dose (15mg/kg). In parallel, we performed transcriptomic profiling of the nucleus accumbens, which again showed a dose x polyphenol interaction. At high dose morphine, BDPP pre-treatment potentiated gene expression changes induced by morphine particularly for genes related to synaptic function. We also profiled microbiome composition and function, as polyphenols are metabolized by the microbiome and can act as prebiotics. The profile revealed polyphenol treatment markedly altered microbiome composition and function, particularly in the low dose morphine group. Finally, we investigated involvement of the SIRT1 histone deacetylase, and the role of specific polyphenol metabolites in these behavioral phenotypes. Taken together, these results demonstrate that polyphenols have robust dose-dependent effects on behavioral and physiological responses to morphine and lay the foundation for future translational work.

neuroscience↗

bioRxiv2022

Microfluidics-free single-cell genomics with templated emulsification

Single-cell RNA sequencing is now a standard method used to reveal the molecular details of cellular heterogeneity, but current approaches have limitations on speed, scale, and ease of use that stem from the complex microfluidic devices or fluid handling steps required for sample processing. We, therefore, developed a method that does not require specialized microfluidic devices, expertise, or hardware. Our approach is based on particle-templated emulsification, which allows single-cell encapsulation and barcoding of cDNA in uniform droplet emulsions with only a vortexer. PIP-seq accommodates a wide range of emulsification formats, including microwell plates and large-volume conical tubes, enabling thousands of samples or millions of cells to be processed in minutes. We demonstrate that PIP-seq produces high-purity transcriptomes in mouse-human mixing studies, is compatible with multi-omics measurements, and can accurately characterize cell types in human breast tissue when compared to a commercial microfluidic platform. Single-cell transcriptional profiling of mixed phenotype acute leukemia using PIP-seq revealed the emergence of heterogeneity within chemotherapy-resistant cell subsets that were hidden by standard immunophenotyping. PIP-seq is a simple, flexible, and scalable next-generation workflow that extends single-cell sequencing to new applications, including screening, diagnostics, and disease monitoring.

genomics↗

bioRxiv2021

Microglial phagocytosis dysfunction during stroke is prevented by rapamycin

Microglial phagocytosis is rapidly emerging as a therapeutic target in neurodegenerative and neurological disorders. An efficient removal of cellular debris is necessary to prevent buildup damage of neighbor neurons and the development of an inflammatory response. As the brain professional phagocytes, microglia are equipped with an array of mechanisms that enable them to recognize and degrade several types of cargo, including neurons undergoing apoptotic cell death. While microglia are very competent phagocytes of apoptotic cells under physiological conditions, here we report their dysfunction in mouse and monkey (Macaca fascicularis and Callithrix jacchus) models of stroke by transient occlusion of the medial cerebral artery (tMCAo). The impairment of both engulfment and degradation was related to energy depletion triggered by oxygen and nutrients deprivation (OND), which led to reduced process motility, lysosomal depletion, and the induction of a protective autophagy response in microglia. Basal autophagy, which is in charge of removing and recycling intracellular elements, was critical to maintain microglial physiology, including survival and phagocytosis, as we determined both in vivo and in vitro using knock-out models of autophagy genes and the autophagy inhibitor MRT68921. Notably, the autophagy inducer rapamycin partially prevented the phagocytosis impairment induced by tMCAo in vivo but not by OND in vitro. These results suggest a more complex role of microglia in stroke than previously acknowledged, classically related to the inflammatory response. In contrast, here we demonstrate the impairment of apoptotic cell phagocytosis, a microglial function critical for brain recovery. We propose that phagocytosis is a therapeutic target yet to be explored and provide evidence that it can be modulated in vivo using rapamycin, setting the stage for future therapies for stroke patients.

neuroscience↗

bioRxiv2021

Granulocyte-colony stimulating factor (G-CSF) enhances cocaine effects in the nucleus accumbens via a dopamine release-based mechanism

Cocaine use disorder is associated with alterations in immune function including altered expression of multiple peripheral cytokines in humans - several of which correlate with drug use. Individuals suffering from cocaine use disorder show altered immune system responses to drug-associated cues, highlighting the interaction between the brain and immune system as a critical factor in the development and expression of cocaine use disorder. We have previously demonstrated in animal models that cocaine use upregulates expression of granulocyte colony stimulating factor (G-CSF) - a pleiotropic cytokine - in the serum and the nucleus accumbens (NAc). G-CSF signaling has been causally linked to behavioral responses to cocaine across multiple behavioral domains. The goal of this study was to define whether increases in G-CSF alter the pharmacodynamic effects of cocaine on the dopamine system and whether this occurs via direct mechanisms within local NAc microcircuits. We find that systemic G-CSF injection increases cocaine effects on dopamine terminals. The enhanced dopamine levels in the presence of cocaine occur through a release-based mechanism, rather than through effects on the dopamine transporter - as uptake rates were unchanged following G-CSF treatment. Critically, this effect could be recapitulated by acute bath application of G-CSF to dopamine terminals, an effect that was occluded by prior G-CSF treatment, suggesting a similar mechanistic basis for direct and systemic exposures. This work highlights the critical interaction between the immune system and psychostimulant effects that can alter drug responses and may play a role in vulnerability to cocaine use disorder.

neuroscience↗

bioRxiv2020

Pericyte-specific vascular expression of SARS-CoV-2 receptor ACE2 - implications for microvascular inflammation and hypercoagulopathy in COVID-19 patients

Accumulating clinical observations implicate vascular inflammation as an underlying cause of coagulopathy in severely ill COVID-19 patients and it was recently suggested that SARS-CoV-2 virus particles infect endothelial cells. Here, we show that endothelial cells do not express angiotensin-converting enzyme-2 (ACE2), the SARS-CoV-2 receptor. Instead, pericytes and microvascular smooth muscle cells express ACE2 in an organotypic manner. Pericyte deficiency leads to increased endothelial expression and release of Von Willebrand factor and intravascular platelet and fibrin aggregation, suggesting that pericytes limit endothelial pro-thrombotic responses. That pericytes and not endothelial cells express ACE2 may provide important clues to the pathology of COVID-19, as pericytes are normally shielded behind an endothelial barrier and may get infected only when this barrier is compromised by COVID-19 risk factors.

pathology↗

bioRxiv2020

Effects of gene by microbiome interactions on behavioral and neurobiological phenotypes in a mouse model for autism spectrum disorder

Autism spectrum disorder (ASD) is a heterogenous neurodevelopmental disorder with complex pathophysiology including both genetic and environmental factors. Recent evidence demonstrates the gut microbiome and its resultant metabolome can influence brain and behavior and have been implicated in ASD. To investigate gene by microbiome interactions in a model for genetic risk of ASD, we utilize mutant mice carrying a deletion of the ASD-associated Shank3 gene (Shank3KO). Shank3KO have altered microbiome composition and function at baseline in addition to social deficits. Further depletion of the microbiome with antibiotics exacerbates social deficits in Shank3KO, and results in transcriptional changes in the frontal cortex. Supplementation with the microbial metabolite acetate leads to reversal of social behavioral phenotypes even in mice with a depleted microbiome, and significantly alters transcriptional regulation in the prefrontal cortex. These results suggest a key role for the gut microbiome and the neuroactive metabolite acetate in regulating ASD-like behaviors.

neuroscience↗