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Cited by 75Genetics and Neurodevelopmental DisordersAutism Spectrum Disorder ResearchNeuroscience and Neuropharmacology Research

Synaptic microcircuit dysfunction in genetic models of neurodevelopmental disorders: focus on Mecp2 and Met

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Shepherd, Gordon MG, Katz, David M·2011·Current Opinion in Neurobiology
DOI 10.1016/j.conb.2011.06.006PMC PMC3199024
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Abstract

Recent findings in the genetics of neurodevelopmental syndromes have ushered in an exciting era of discovery in which substrates of neurologic dysfunction are being identified at the synaptic and microcircuit levels in mouse models of these disorders. We review recent progress in this area, focusing on two examples of mouse models of autism spectrum disorders (ASDs): Mecp2 models of Rett syndrome, and a Met-knockout model of non-syndromic forms of autism. In both cases, a dominant theme is changes in synaptic strength, associated with hyper-connectivity or hypo-connectivity in specific microcircuits. Alterations in intrinsic neuronal excitability are also found, but do not appear to be as common. The microcircuit-specific nature of synaptic changes observed in these ASD models indicates that it will be necessary to define mechanisms of circuit dysfunction on a case-by-case basis, not only in neocortex but also in brainstem and other sub-cortical areas. Thus, functional microcircuit analysis is emerging as an important line of investigation, highly complementary to neurogenetic and molecular strategies, and holds promise for generating models of the underlying pathophysiology and for guiding development of novel therapeutic strategies.

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Crossref · 10.1016/j.conb.2011.06.006

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  • Mecp2 null males are normal at birth and weaning, but develop limb clasping, tremors, lethargy and abnormal breathing, symptoms that progressively worsen until death at 6-16 weeks of age.

    “Null males are normal at birth and weaning, but develop limb clasping, tremors, lethargy and abnormal breathing, symptoms that progressively worsen until death at 6 – 16 weeks of age.”

    From A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome (2013) · cites this paper as [4]

    The Neocortical microcircuits section says changes in Mecp2-null mice are evident at week 2, before overt symptoms, and grow stronger by weeks 3–4. The Synaptic dysfunction in respiratory networks section discusses breathing abnormalities in the mouse models. Neither section supports the full symptom list, normality at birth and weaning, or death at 6–16 weeks; page numbers are unavailable in our copy. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Male Mecp2/Y mice have a fully penetrant phenotype.

    “Although female Mecp2/+ mice show phenotypic variance in part due to random X-chromosome inactivation, male Mecp2/Y mice have a fully penetrant phenotype.”

    From A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome (2013) · cites this paper as [4]

    The section on neocortical microcircuits in MeCP2 deficiency models (page not provided) reports abnormalities in Mecp2-null mice, supporting the claim that the model has a phenotype. It does not state that every male Mecp2/Y mouse is affected or establish full penetrance. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Mouse models recapitulate many of the symptoms of RTT.

    “Mouse models recapitulate many of the symptoms of RTT and their study has provided insight into the physiological basis of disease3–5.”

    From A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome (2013) · cites this paper as [4]

  • MECP2 plays roles in the postnatal maturation and/or maintenance of neuronal properties and circuits.

    “Therefore, MECP2 plays roles in the postnatal maturation and/or maintenance of neuronal properties and circuits4.”

    From A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome (2013) · cites this paper as [4]

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Authors
Shepherd, G. M., & Katz, D. M.
Affiliations
  • Northwestern University (US)
  • Case Western Reserve University (US)
Corresponding author
Katz, David M
ORCID
Venue
Current Opinion in Neurobiology
Publisher
Elsevier BV
Published
2011-12
Volume
21
Issue
6
Pages
827-833
ISSN
0959-4388 (ISSN-L)
DOI
10.1016/j.conb.2011.06.006
PMC
PMC3199024
OpenAlex
W2152020947
Cited by
75
References
15
Citations by year
2024: 1 · 2023: 4 · 2022: 2 · 2021: 3 · 2020: 2 · 2019: 7 · 2018: 3 · 2017: 7 · 2016: 8 · 2015: 7 · 2014: 9 · 2013: 9 · 2012: 12
FWCI
1.05
Type
journal article
Language
en
Open access
Licence
Locations
  • Current Opinion in Neurobiology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Neurological Disorders and Stroke (NS061963, R01NS057398, R01NS061963, R56NS057398, R37NS061963, NS-057398)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
neurodevelopmental disorders, autism spectrum disorder, MeCP2, Rett syndrome, c-Met, non-syndromic autism, synaptic efficacy, hyperconnectivity, neuronal excitability, mouse model, circuit dysfunction
MeSH terms
Animals, Child, Child Development Disorders, Pervasive, Humans, Synapses, Proto-Oncogene Proteins c-met, Mice, Methyl-CpG-Binding Protein 2

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