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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| 40 | 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) | unchanged in Ube3a2xTg barrel cortex (Smith et al., 2011). Whole-cell patch clamp recording revealedβ¦ |
| 41 | 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) | Currently, no conditional knockouts of Ube3a have been reported, so there is limited knowledge aboutβ¦ |
| 42 | 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) | Numerous targets of Ube3a-dependent ubiquitination have been identified (Kumar et al., 1999; Mani etβ¦ |
| 43 | 3. Overview of Monogenic Mouse Models of ASDs β 3.3 Synaptic Organizing and Scaffolding: Shanks, Neurexins/Neuroligins β 3.3.1 Shanks (Phelan-McDermid syndrome and non-syndromic ASDs) | Mutations in the SHANK/ProSAP family genes (SHANK1β3), particularly SHANK2 and SHANK3, have beenβ¦ |
| 44 | 3. Overview of Monogenic Mouse Models of ASDs β 3.3 Synaptic Organizing and Scaffolding: Shanks, Neurexins/Neuroligins β 3.3.1 Shanks (Phelan-McDermid syndrome and non-syndromic ASDs) | Mouse models for each of the three Shank proteins have been created to better understand the role ofβ¦ |
| 45 | 3. Overview of Monogenic Mouse Models of ASDs β 3.3 Synaptic Organizing and Scaffolding: Shanks, Neurexins/Neuroligins β 3.3.1 Shanks (Phelan-McDermid syndrome and non-syndromic ASDs) | Ten different lines of Shank3 mutant mice have been reported, but due to the transcriptionalβ¦ |
| 46 | 3. Overview of Monogenic Mouse Models of ASDs β 3.3 Synaptic Organizing and Scaffolding: Shanks, Neurexins/Neuroligins β 3.3.1 Shanks (Phelan-McDermid syndrome and non-syndromic ASDs) | Although there are no published studies that have explored the role of the Shank proteins inβ¦ |
| 47 | 3. Overview of Monogenic Mouse Models of ASDs β 3.3 Synaptic Organizing and Scaffolding: Shanks, Neurexins/Neuroligins β 3.3.1 Shanks (Phelan-McDermid syndrome and non-syndromic ASDs) | et al., 2011). However, deletion of exon 11 (Schmeisser et al., 2012) or exon 21 (Kouser et al,β¦ |
| 48 | 3. Overview of Monogenic Mouse Models of ASDs β 3.3 Synaptic Organizing and Scaffolding: Shanks, Neurexins/Neuroligins β 3.3.1 Shanks (Phelan-McDermid syndrome and non-syndromic ASDs) | Accumulating evidence in vivo suggests that Shank proteins are required for proper synaptic functionβ¦ |
| 49 | 3. Overview of Monogenic Mouse Models of ASDs β 3.3 Synaptic Organizing and Scaffolding: Shanks, Neurexins/Neuroligins β 3.3.1 Shanks (Phelan-McDermid syndrome and non-syndromic ASDs) | The findings from Shank3 mutants are also somewhat inconsistent, but many of the differences can beβ¦ |
| 50 | 3. Overview of Monogenic Mouse Models of ASDs β 3.3 Synaptic Organizing and Scaffolding: Shanks, Neurexins/Neuroligins β 3.3.1 Shanks (Phelan-McDermid syndrome and non-syndromic ASDs) | those observed by Wang et al. and Jaramillo et al. in the hippocampus, but resulted in decreasedβ¦ |
| 51 | 3. Overview of Monogenic Mouse Models of ASDs β 3.3 Synaptic Organizing and Scaffolding: Shanks, Neurexins/Neuroligins β 3.3.1 Shanks (Phelan-McDermid syndrome and non-syndromic ASDs) | The mechanism through which deletion of Shank proteins leads to synaptic dysfunction is likely dueβ¦ |
| 52 | 3. Overview of Monogenic Mouse Models of ASDs β 3.3 Synaptic Organizing and Scaffolding: Shanks, Neurexins/Neuroligins β 3.3.1 Shanks (Phelan-McDermid syndrome and non-syndromic ASDs) | Moreover, changes in the densities of receptors and synaptic proteins have been reported in vivo.β¦ |
| 53 | 3. Overview of Monogenic Mouse Models of ASDs β 3.3 Synaptic Organizing and Scaffolding: Shanks, Neurexins/Neuroligins β 3.3.1 Shanks (Phelan-McDermid syndrome and non-syndromic ASDs) | Mice with different Shank3 mutations have varying degrees of altered expression of receptors,β¦ |
| 54 | 3. Overview of Monogenic Mouse Models of ASDs β 3.3 Synaptic Organizing and Scaffolding: Shanks, Neurexins/Neuroligins β 3.3.2 Neurexins/Neuroligins (non-syndromic ASDs) | Mutations in the genes encoding the presynaptic cell-adhesion molecules, neurexins, and theirβ¦ |
| 55 | 3. Overview of Monogenic Mouse Models of ASDs β 3.3 Synaptic Organizing and Scaffolding: Shanks, Neurexins/Neuroligins β 3.3.2 Neurexins/Neuroligins (non-syndromic ASDs) | A multitude of mice with mutations in the neurexins, neuroligins, and related genes have beenβ¦ |
| 56 | 3. Overview of Monogenic Mouse Models of ASDs β 3.3 Synaptic Organizing and Scaffolding: Shanks, Neurexins/Neuroligins β 3.3.2 Neurexins/Neuroligins (non-syndromic ASDs) | In addition to the study that reported ASD-like behaviors in mice overexpressing a dominant-negativeβ¦ |
| 57 | 3. Overview of Monogenic Mouse Models of ASDs β 3.3 Synaptic Organizing and Scaffolding: Shanks, Neurexins/Neuroligins β 3.3.2 Neurexins/Neuroligins (non-syndromic ASDs) | Unlike the other mouse models of ASDs, individual neurexin and neuroligin mutants do not have manyβ¦ |
| 58 | 3. Overview of Monogenic Mouse Models of ASDs β 3.3 Synaptic Organizing and Scaffolding: Shanks, Neurexins/Neuroligins β 3.3.2 Neurexins/Neuroligins (non-syndromic ASDs) | still express Nlgn1 (Kwon et al., 2012). Whereas mice lacking Nlgn2 have normal numbers of bothβ¦ |
| 59 | 3. Overview of Monogenic Mouse Models of ASDs β 3.3 Synaptic Organizing and Scaffolding: Shanks, Neurexins/Neuroligins β 3.3.2 Neurexins/Neuroligins (non-syndromic ASDs) | Although changes in cellular and spine morphology in neurexin and neuroligin mouse models of ASD areβ¦ |
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| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
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| 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 |
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| 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 |