Monogenic mouse models of autism spectrum disorders: Common mechanisms and missing links.
paper
Cited
Public
- Authors
- Hulbert, S W; Jiang, Y-H
- Year
- 2016
- Journal
- Neuroscience
- PMID
- 26733386
- DOI
- 10.1016/j.neuroscience.2015.12.040
- PMCID
- PMC4803542
Autism spectrum disorders (ASDs) present unique challenges in the fields of genetics and neurobiology because of the clinical and molecular heterogeneity underlying these disorders. Genetic mutations found in ASD patients provide opportunities to dissect the molecular and circuit mechanisms underlying autistic behaviors using animal models. Ongoing studies of genetically modified models have offered critical insight into possible common mechanisms arising from different mutations, but links between molecular abnormalities and behavioral phenotypes remain elusive. The challenges encountered in modeling autism in mice demand a new analytic paradigm that integrates behavioral assessment with circuit-level analysis in genetically modified models with strong construct validity.
Monogenic mouse models of ASDs have disruptions in overlapping molecular pathwaysThe epigenetic and transcriptional regulator MeCP2 controls the expression of hundreds of different proteins, including BDNF. When BDNF binds to TrkB, its receptor, the resulting signaling pathways converge with pathways known to influence local protein synthesis. The RNA-binding protein FMRP is directly involved in suppressing the translation of mRNA, but other proteins implicated in ASDs, including hamartin and tuberin (the proteins encoded by TSC1 and TSC2), as well as PTEN are upstream signaling molecules that converge on this pathway. The synaptic organizing proteins from the Shank and neurexin/neuroligin families influence these pathways indirectly by affecting the localization and function of glutamate receptors. Similarly, the ubiquitin protein ligase Ube3a normally suppresses the internalization of AMPA receptors, thereby affecting neuronal signaling and plasticity.
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| 20 | 3. Overview of Monogenic Mouse Models of ASDs β 3.2 Post-Transcriptional Protein Modifiers or Regulators: Fmr1, Tsc1/2, Ube3a, and Pten β 3.2.1 Fmr1 (Fragile X syndrome) | The enhanced mGluR-mediated LTD observed in Fmr1 knockouts (Huber et al., 2002) paved the way forβ¦ |
| 21 | 3. Overview of Monogenic Mouse Models of ASDs β 3.2 Post-Transcriptional Protein Modifiers or Regulators: Fmr1, Tsc1/2, Ube3a, and Pten β 3.2.1 Fmr1 (Fragile X syndrome) | subsequent dysregulated translation. For instance, the BDNF/TrkB signaling pathway converges withβ¦ |
| 22 | 3. Overview of Monogenic Mouse Models of ASDs β 3.2 Post-Transcriptional Protein Modifiers or Regulators: Fmr1, Tsc1/2, Ube3a, and Pten β 3.2.1 Fmr1 (Fragile X syndrome) | Compared to other models, little work has been published utilizing Fmr1 conditional knockout mice toβ¦ |
| 23 | 3. Overview of Monogenic Mouse Models of ASDs β 3.2 Post-Transcriptional Protein Modifiers or Regulators: Fmr1, Tsc1/2, Ube3a, and Pten β 3.2.2 Tsc1/Tsc2 (Tuberous sclerosis complex) | Tuberous sclerosis complex (TSC) is a disorder characterized by the formation of benign tumors,β¦ |
| 24 | 3. Overview of Monogenic Mouse Models of ASDs β 3.2 Post-Transcriptional Protein Modifiers or Regulators: Fmr1, Tsc1/2, Ube3a, and Pten β 3.2.2 Tsc1/Tsc2 (Tuberous sclerosis complex) | Homozygous deletion of Tsc1 exons 6β8 (Kobayashi et al., 2001), Tsc1 exons 17β18 (Kwiatkowski etβ¦ |
| 25 | 3. Overview of Monogenic Mouse Models of ASDs β 3.2 Post-Transcriptional Protein Modifiers or Regulators: Fmr1, Tsc1/2, Ube3a, and Pten β 3.2.2 Tsc1/Tsc2 (Tuberous sclerosis complex) | Depletion of Tsc1 or Tsc2 in cultured post-mitotic hippocampal neurons results in increased somaβ¦ |
| 26 | 3. Overview of Monogenic Mouse Models of ASDs β 3.2 Post-Transcriptional Protein Modifiers or Regulators: Fmr1, Tsc1/2, Ube3a, and Pten β 3.2.2 Tsc1/Tsc2 (Tuberous sclerosis complex) | Decreased expression of Tsc1 or Tsc2 has drastic impacts on synaptic function as well, but theβ¦ |
| 27 | 3. Overview of Monogenic Mouse Models of ASDs β 3.2 Post-Transcriptional Protein Modifiers or Regulators: Fmr1, Tsc1/2, Ube3a, and Pten β 3.2.2 Tsc1/Tsc2 (Tuberous sclerosis complex) | At the cellular level, loss-of-function mutations in Tsc1 and Tsc2 lead to hyperactivation ofβ¦ |
| 28 | 3. Overview of Monogenic Mouse Models of ASDs β 3.2 Post-Transcriptional Protein Modifiers or Regulators: Fmr1, Tsc1/2, Ube3a, and Pten β 3.2.2 Tsc1/Tsc2 (Tuberous sclerosis complex) | Various conditional knockouts of Tsc1 or Tsc2 have been used to determine cell types and brainβ¦ |
| 29 | 3. Overview of Monogenic Mouse Models of ASDs β 3.2 Post-Transcriptional Protein Modifiers or Regulators: Fmr1, Tsc1/2, Ube3a, and Pten β 3.2.2 Tsc1/Tsc2 (Tuberous sclerosis complex) | loss of heterozygosity (LOH) occurs in a cell-specific manner in TSC (Crino, 2013) and it isβ¦ |
| 30 | 3. Overview of Monogenic Mouse Models of ASDs β 3.2 Post-Transcriptional Protein Modifiers or Regulators: Fmr1, Tsc1/2, Ube3a, and Pten β 3.2.3 Pten (PTEN hamartoma tumor syndromes and non-syndromic ASDs) | Mutations in phosphatase and tensin homolog (PTEN) were first identified in a number of patientsβ¦ |
| 31 | 3. Overview of Monogenic Mouse Models of ASDs β 3.2 Post-Transcriptional Protein Modifiers or Regulators: Fmr1, Tsc1/2, Ube3a, and Pten β 3.2.3 Pten (PTEN hamartoma tumor syndromes and non-syndromic ASDs) | The first Pten knockout mouse models showed that homozygous deletion of exons 4 and 5 (Di Cristofanoβ¦ |
| 32 | 3. Overview of Monogenic Mouse Models of ASDs β 3.2 Post-Transcriptional Protein Modifiers or Regulators: Fmr1, Tsc1/2, Ube3a, and Pten β 3.2.3 Pten (PTEN hamartoma tumor syndromes and non-syndromic ASDs) | cerebellum and neurons in the dentate gyrus of the hippocampus (Gfap-Cre; Lugo et al., 2014).β¦ |
| 33 | 3. Overview of Monogenic Mouse Models of ASDs β 3.2 Post-Transcriptional Protein Modifiers or Regulators: Fmr1, Tsc1/2, Ube3a, and Pten β 3.2.3 Pten (PTEN hamartoma tumor syndromes and non-syndromic ASDs) | Detailed studies of the PTEN-related ASD mouse models have revealed several cellular structuralβ¦ |
| 34 | 3. Overview of Monogenic Mouse Models of ASDs β 3.2 Post-Transcriptional Protein Modifiers or Regulators: Fmr1, Tsc1/2, Ube3a, and Pten β 3.2.3 Pten (PTEN hamartoma tumor syndromes and non-syndromic ASDs) | Not only do neurons lacking Pten have drastic morphological aberrations, but they also haveβ¦ |
| 35 | 3. Overview of Monogenic Mouse Models of ASDs β 3.2 Post-Transcriptional Protein Modifiers or Regulators: Fmr1, Tsc1/2, Ube3a, and Pten β 3.2.3 Pten (PTEN hamartoma tumor syndromes and non-syndromic ASDs) | Pten is involved in the suppressing the Akt signaling pathway upstream of mTOR activity, whichβ¦ |
| 36 | 3. Overview of Monogenic Mouse Models of ASDs β 3.2 Post-Transcriptional Protein Modifiers or Regulators: Fmr1, Tsc1/2, Ube3a, and Pten β 3.2.4 Ube3a (Angelman syndrome and non-syndromic ASDs) | Patients diagnosed with Angelman syndrome (AS) frequently meet the diagnostic criteria for ASDβ¦ |
| 37 | 3. Overview of Monogenic Mouse Models of ASDs β 3.2 Post-Transcriptional Protein Modifiers or Regulators: Fmr1, Tsc1/2, Ube3a, and Pten β 3.2.4 Ube3a (Angelman syndrome and non-syndromic ASDs) | Mouse models of AS that recapitulate the major features of the disorder, including some ASD-likeβ¦ |
| 38 | 3. Overview of Monogenic Mouse Models of ASDs β 3.2 Post-Transcriptional Protein Modifiers or Regulators: Fmr1, Tsc1/2, Ube3a, and Pten β 3.2.4 Ube3a (Angelman syndrome and non-syndromic ASDs) | Maternal deficiency of Ube3a affects dendritic and spine morphology. Specifically, Ube3amβ/p+ miceβ¦ |
| 39 | 3. Overview of Monogenic Mouse Models of ASDs β 3.2 Post-Transcriptional Protein Modifiers or Regulators: Fmr1, Tsc1/2, Ube3a, and Pten β 3.2.4 Ube3a (Angelman syndrome and non-syndromic ASDs) | Perhaps the best studied aspect of AS and other Ube3a mouse models are the electrophysiologicalβ¦ |
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External
| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| Genetics of Autism Spectrum Disorder underscores the role of altered spontaneous neuronal activity as a catalyst for the neurodevelopmental anomalies. | Dey S et al. | β | 2026 | β |
| Synaptic editing of frontostriatal circuitry prevents excessive grooming in SAPAP3-deficient mice | Walder-Christensen KK et al. | β | 2025 | β |
| Development of an <i>in vitro</i> compound screening system that replicate the <i>in vivo</i> spine phenotype of idiopathic ASD model mice. | Maeda K et al. | β | 2024 | β |
| Is tuberous sclerosis complex-associated autism a preventable and treatable disorder? | Curatolo P et al. | β | 2024 | β |
| Tactile sensory processing deficits in genetic mouse models of autism spectrum disorder. | FalcΓ£o M et al. | β | 2024 | β |
| The early life exposome and autism risk: a role for the maternal microbiome? | Di GesΓΉ CM et al. | β | 2024 | β |
| Comparing synaptic proteomes across five mouse models for autism reveals converging molecular similarities including deficits in oxidative phosphorylation and Rho GTPase signaling. | Carbonell AU et al. | β | 2023 | β |
| Maternal methyl donor supplementation regulates the effects of cafeteria diet on behavioral changes and nutritional status in male offspring. | Herrera K et al. | β | 2023 | β |
| Resting-State Functional MRI and PET Imaging as Noninvasive Tools to Study (Ab)Normal Neurodevelopment in Humans and Rodents. | Millevert C et al. | β | 2023 | β |
| The autism spectrum disorder risk gene <i>NEXMIF</i> over-synchronizes hippocampal CA1 network and alters neuronal coding. | Mount RA et al. | β | 2023 | β |
| A perspective on molecular signalling dysfunction, its clinical relevance and therapeutics in autism spectrum disorder. | Purushotham SS et al. | β | 2022 | β |
| Brain region and gene dosage-differential transcriptomic changes in <i>Shank2</i>-mutant mice. | Yoo YE et al. | β | 2022 | β |
| Early and Late Corrections in Mouse Models of Autism Spectrum Disorder. | Chung C et al. | β | 2022 | β |
| The role of the endocannabinoid system as a therapeutic target for autism spectrum disorder: Lessons from behavioral studies on mouse models. | Pietropaolo S et al. | β | 2022 | β |
| The State of the Dopaminergic and Glutamatergic Systems in the Valproic Acid Mouse Model of Autism Spectrum Disorder. | Maisterrena A et al. | β | 2022 | β |
| Animal models of neurodevelopmental disorders with behavioral phenotypes. | Harris JC | β | 2021 | β |
| Spectrum of social alterations in the Neurobeachin haploinsufficiency mouse model of autism. | Odent P et al. | β | 2021 | β |
| Zebrafish, an In Vivo Platform to Screen Drugs and Proteins for Biomedical Use. | Lee HC et al. | β | 2021 | β |
| A Novel Chd8 Mutant Mouse Displays Altered Ultrasonic Vocalizations and Enhanced Motor Coordination. | Hulbert SW et al. | β | 2020 | β |
| Convergent brain microstructure across multiple genetic models of schizophrenia and autism spectrum disorder: A feasibility study. | Barnett BR et al. | β | 2020 | β |
| Dysregulation of protein synthesis and dendritic spine morphogenesis in ASD: studies in human pluripotent stem cells. | Lo LH et al. | β | 2020 | β |
| <i>Ex vivo</i> Quantitative Proteomic Analysis of Serotonin Transporter Interactome: Network Impact of the SERT Ala56 Coding Variant. | Quinlan MA et al. | β | 2020 | β |
| Lipopolysaccharide-induced inflammation leads to acute elevations in pro-inflammatory cytokine expression in a mouse model of Fragile X syndrome. | Hodges SL et al. | β | 2020 | β |
| Pharmacological, non-pharmacological and stem cell therapies for the management of autism spectrum disorders: A focus on human studies. | Pistollato F et al. | β | 2020 | β |
| Targeting Gamma-Related Pathophysiology in Autism Spectrum Disorder Using Transcranial Electrical Stimulation: Opportunities and Challenges. | Kayarian FB et al. | β | 2020 | β |
| Using Zebrafish to Model Autism Spectrum Disorder: A Comparison of ASD Risk Genes Between Zebrafish and Their Mammalian Counterparts. | Rea V et al. | β | 2020 | β |
| A single early-life seizure results in long-term behavioral changes in the adult Fmr1 knockout mouse. | Hodges SL et al. | β | 2019 | β |
| A TBR1-K228E Mutation Induces <i>Tbr1</i> Upregulation, Altered Cortical Distribution of Interneurons, Increased Inhibitory Synaptic Transmission, and Autistic-Like Behavioral Deficits in Mice. | Yook C et al. | β | 2019 | β |
| A unified circuit for social behavior. | Modi ME et al. | β | 2019 | β |
| Autism Spectrum Disorder-Related Syndromes: Modeling with <i>Drosophila</i> and Rodents. | Ueoka I et al. | β | 2019 | β |
| Autism spectrum disorders: autistic phenotypes and complicated mechanisms. | Zhang XC et al. | β | 2019 | β |
| Emerging connections between cerebellar development, behaviour and complex brain disorders. | Sathyanesan A et al. | β | 2019 | β |
| Home-cage hypoactivity in mouse genetic models of autism spectrum disorder. | Angelakos CC et al. | β | 2019 | β |
| Preclinical neuroimaging of gene-environment interactions in psychiatric disease. | Yi SY et al. | β | 2019 | β |
| Advances in nonhuman primate models of autism: Integrating neuroscience and behavior. | Bauman MD et al. | β | 2018 | β |
| Autism spectrum disorder: prospects for treatment using gene therapy. | Benger M et al. | β | 2018 | β |
| Cell-Type-Specific <i>Shank2</i> Deletion in Mice Leads to Differential Synaptic and Behavioral Phenotypes. | Kim R et al. | β | 2018 | β |
| Current Enlightenment About Etiology and Pharmacological Treatment of Autism Spectrum Disorder. | Eissa N et al. | β | 2018 | β |
| Dysbiosis of microbiome and probiotic treatment in a genetic model of autism spectrum disorders. | Tabouy L et al. | β | 2018 | β |
| Environmental enrichment has minimal effects on behavior in the Shank3 complete knockout model of autism spectrum disorder. | Hulbert SW et al. | β | 2018 | β |
| Genomics in neurodevelopmental disorders: an avenue to personalized medicine. | TΔrlungeanu DC et al. | β | 2018 | β |
| Intracellular calcium dysregulation in autism spectrum disorder: An analysis of converging organelle signaling pathways. | Nguyen RL et al. | β | 2018 | β |
| Modeling autism in non-human primates: Opportunities and challenges. | Zhao H et al. | β | 2018 | β |
| Shank3-deficient thalamocortical neurons show HCN channelopathy and alterations in intrinsic electrical properties. | Zhu M et al. | β | 2018 | β |
| Bridging Autism Spectrum Disorders and Schizophrenia through inflammation and biomarkers - pre-clinical and clinical investigations. | Prata J et al. | β | 2017 | β |
| Cellular and Circuitry Bases of Autism: Lessons Learned from the Temporospatial Manipulation of Autism Genes in the Brain. | Hulbert SW et al. | β | 2017 | β |
| Deficiency of Shank2 causes mania-like behavior that responds to mood stabilizers. | Pappas AL et al. | β | 2017 | β |
| Do group I metabotropic glutamate receptors mediate LTD? | Jones OD | β | 2017 | β |
| Natural products as mediators of disease. | Garg N et al. | β | 2017 | β |
| PTEN: Local and Global Modulation of Neuronal Function in Health and Disease. | Knafo S et al. | β | 2017 | β |
| Translating genetic and preclinical findings into autism therapies. | Chahrour M et al. | β | 2017 | β |
| Whither the genotype-phenotype relationship? An historical and methodological appraisal. | Fisch GS | β | 2017 | β |
| Animal models of psychiatric disorders. | Gordon JA et al. | β | 2016 | β |
| Bioinformatic Analysis of DNA Methylation in Neural Progenitor Cell Models of Alcohol Abuse. | Oni EN et al. | β | 2016 | β |
| Lessons learned from studying syndromic autism spectrum disorders. | Sztainberg Y et al. | β | 2016 | β |