Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits
Open accessAbstract
Although many genes predisposing to autism spectrum disorders (ASD) have been identified, the biological mechanism(s) remain unclear. Mouse models based on human disease-causing mutations provide the potential for understanding gene function and novel treatment development. Here, we characterize a mouse knockout of the Cntnap2 gene, which is strongly associated with ASD and allied neurodevelopmental disorders. Cntnap2(-/-) mice show deficits in the three core ASD behavioral domains, as well as hyperactivity and epileptic seizures, as have been reported in humans with CNTNAP2 mutations. Neuropathological and physiological analyses of these mice before the onset of seizures reveal neuronal migration abnormalities, reduced number of interneurons, and abnormal neuronal network activity. In addition, treatment with the FDA-approved drug risperidone ameliorates the targeted repetitive behaviors in the mutant mice. These data demonstrate a functional role for CNTNAP2 in brain development and provide a new tool for mechanistic and therapeutic research in ASD.
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The time point of aberrant functional and structural connectivity coincides with the expression profile of the knockout genes, suggesting that the timing in which ASD risk genes are functionally active is critical for development of aberrant connectivity patterns and possibly behavioral symptoms later in life.
“Interestingly, the time point of the aberrant functional and structural connectivity coincides with the expression profile of the knockout genes, suggesting that the timing in which ASD risk-genes are functionally active is critical for the development of aberrant connectivity patterns and possibly behavioral symptoms later in life.”
From Dysfunctional Autism Risk Genes Cause Circuit-Specific Connectivity Deficits With Distinct Developmental Trajectories (2018) · cites this paper as Penagarikano et al. 2011
FMR1 plays a pivotal role in early embryotic neurodevelopment, whereas physiological expression of CNTNAP2 begins around E14 but peaks during adulthood at P56.
“FMR1 plays a pivotal role in early embryotic neurodevelopment (Hinds et al. 1993) whereas the physiological expression of CNTNAP2 begins at around E14 but peaks during adulthood (P56) (Penagarikano et al. 2011).”
From Dysfunctional Autism Risk Genes Cause Circuit-Specific Connectivity Deficits With Distinct Developmental Trajectories (2018) · cites this paper as Penagarikano et al. 2011
CNTNAP2-KO mice have a reduced number of GABAergic interneurons and impaired migration of cortical projection neurons.
“CNTNAP2-KO mice have a reduced number of GABAergic interneurons and impaired migration of cortical projection neurons, which likely cause a higher incidence of seizures and abnormal behaviors such as impaired social interactions and elevated repetitive self-grooming (Penagarikano et al. 2011).”
From Dysfunctional Autism Risk Genes Cause Circuit-Specific Connectivity Deficits With Distinct Developmental Trajectories (2018) · cites this paper as Penagarikano et al. 2011
Mice lacking Cntnap2 display deficits in social interaction and communication, hyperactivity, and seizures.
“Mice lacking Contactin-associated protein 2 (Cntnap2) display deficits in social interaction and communication, hyperactivity, and seizures (Penagarikano et al., 2011).”
From CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics (2012) · cites this paper as Penagarikano et al., 2011
Mice lacking Cntnap2 exhibit neuronal migration abnormalities, reduced numbers of interneurons, and abnormal neuronal network activity.
“Mice lacking Cntnap2 exhibit neuronal migration abnormalities, reduced number of interneurons, and abnormal neuronal network activity (Penagarikano et al., 2011).”
From CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics (2012) · cites this paper as Penagarikano et al., 2011
Cntnap2−/− mice show abnormal migration of neurons in the corpus callosum and somatosensory cortex, have fewer parvalbumin-immunoreactive interneurons in the hippocampus and striatum, fewer GABAergic interneurons in the somatosensory cortex, and fewer oxytocin-expressing neurons in the hypothalamic paraventricular nucleus.
“When compared to WT controls, Cntnap2−/− mice show abnormal migration of neurons in the corpus callosum and somatosensory cortex, have fewer parvalbumin-immunoreactive interneurons in the hippocampus and striatum, fewer GABAergic interneurons in the somatosensory cortex [278] and fewer oxytocin-expressing neurons in the hypothalamic paraventricular nucleus [279].”
From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [278]
Manipulations of other genes associated with intellectual disability and ASD (e.g., MECP2, NLGN3, Shank3, CNTNAP2) reveal diverse abnormalities within cortical GABAergic circuits.
“Manipulations of other genes associated with intellectual disability and ASD (for example, MECP2, NLGN3, Shank3; CNTNAP2) reveal diverse abnormalities within cortical GABAergic circuits.27, 28, 113, 114, 115”
From Oxidative stress-driven parvalbumin interneuron impairment as a common mechanism in models of schizophrenia (2017) · cites this paper as [28]
Both increase and decrease in the number of PV-IR cells are reported in these models.
“Both increase and decrease in number of PV-IR cells are reported.”
From Oxidative stress-driven parvalbumin interneuron impairment as a common mechanism in models of schizophrenia (2017) · cites this paper as [28]
Experimental interventions rescue subsets of behavioral abnormalities in mouse models of autism.
“Experimental interventions, working through diverse genetic and pharmacological mechanisms, rescue subsets of behavioral abnormalities in these mouse models (31, 43, 48–52).”
From Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism (2012) · cites this paper as [43]
Target strategies draw from therapeutics under investigation for other neurodevelopmental disorders and hypotheses emerging from mutations in synaptic genes identified in small numbers of individuals with autism spectrum disorders.
“Target strategies draw from therapeutics under investigation for other neurodevelopmental disorders and hypotheses emerging from mutations in synaptic genes identified in small numbers of individuals with autism spectrum disorders (43, 49, 52).”
From Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism (2012) · cites this paper as [43]
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- Authors
- Peñagarikano, O., Abrahams, B. S., Herman, E. I., Winden, K. D., Gdalyahu, A., Dong, H., Sonnenblick, L. I., Gruver, R., Almajano, J., Bragin, A., Golshani, P., Trachtenberg, J. T., Peles, E., & Geschwind, D. H.
- Affiliations
- University of California, Los Angeles (US)
- Weizmann Institute of Science (IL)
- Corresponding author
- Geschwind, Daniel H.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2011-09
- Volume
- 147
- Issue
- 1
- Pages
- 235-246
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3390029
- OpenAlex
- W2099756187
- Cited by
- 1,075
- References
- 71
- Citations by year
- 2026: 61 · 2025: 85 · 2024: 70 · 2023: 83 · 2022: 64 · 2021: 83 · 2020: 65 · 2019: 67 · 2018: 67 · 2017: 101 · 2016: 74 · 2015: 77 · 2014: 56 · 2013: 60 · 2012: 53
- FWCI
- 35.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 721 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R01MH081754-02R, R01MH081754)
- National Institute of Neurological Disorders and Stroke (R01NS050220, NS50220)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (1P50-HD055784-01, P50HD055784)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Keywords
- CNTNAP2, autism spectrum disorder, mouse knockout, epilepsy, neuronal migration, neuronal network activity, hyperactivity, repetitive behavior, risperidone, neurodevelopmental disorders, brain development
- MeSH terms
- Animals, Autistic Disorder, Brain, Cell Movement, Disease Models, Animal, Epilepsy, Humans, Interneurons, Membrane Proteins, Nerve Tissue Proteins, Neurons, Mice, Knockout, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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