Loss of<i>Cntnap2</i>Causes Axonal Excitability Deficits, Developmental Delay in Cortical Myelination, and Abnormal Stereotyped Motor Behavior

Scott, Ricardo; Sánchez-Aguilera, Alberto; Elst, Kim van; Lim, Lynette; Dehorter, Nathalie; Bae, Sung Eun; Bartolini, Giorgia; Peles, Elior; Kas, Martien; Bruining, Hilgo; Marı́n, Oscar

doi:10.1093/cercor/bhx341

Cited by 78 publications

(97 citation statements)

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“…The fact that in the visual cortex neither intrinsic excitability nor the spike features were altered in these mice supports a developmental role for CASPR2 in the maturation and stability of GABAergic synapses (Bridi et al, 2017). In contrast to these findings, Scott et al (2017) did not find any deficit of inhibitory GABAergic interneurons in the somatosensory cortex or any deficits in inhibitory postsynaptic currents in adult Cntnap2 KO mice (Scott et al, 2017). Further investigations are needed to explain these discrepancies.…”

Section: Caspr2 In Network Formationmentioning

confidence: 69%

“…In contrast, by recording the global axonal electrical activity in acute cortical slice of 8‐week‐old Cntnap2 KO animals, a decrease in fiber volleys amplitudes was observed with a slowdown of the AP repolarization phase that could be attributed to improper Kv1 distribution. This led to an increase in neurotransmitter release and a consecutive increase in postsynaptic excitatory responses (Scott et al., ). According to these findings, Kv1 surface expression was decreased at the soma of a subpopulation of DRG neurons in Cntnap2 KO mice, rendering them hyperexcitable (Dawes et al., ).…”

Section: Structure Expression and Function Of Caspr2mentioning

confidence: 99%

See 1 more Smart Citation

Contactin‐associated protein‐like 2, a protein of the neurexin family involved in several human diseases

Saint‐Martin

Joubert

Pellier‐Monnin

et al. 2018

Eur J of Neuroscience

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Contactin-associated protein-like 2 (CASPR2) is a cell adhesion protein of the neurexin family. Proteins of this family have been shown to play a role in the development of the nervous system, in synaptic functions, and in neurological diseases. Over recent years, CASPR2 function has gained an increasing interest as demonstrated by the growing number of publications. Here, we gather published data to comprehensively review CASPR2 functions within the nervous system in relation to CASPR2-related diseases in humans. On the one hand, studies on Cntnap2 (coding for CASPR2) knockout mice revealed its role during development, especially, in setting-up the inhibitory network. Consistent with this result, mutations in the CNTNAP2 gene coding for CASPR2 in human have been identified in neurodevelopmental disorders such as autism, intellectual disability, and epilepsy. On the other hand, CASPR2 was shown to play a role beyond development, in the localization of voltage-gated potassium channel (VGKC) complex that is composed of TAG-1, Kv1.1, and Kv1.2. This complex was found in several subcellular compartments essential for action potential propagation: the node of Ranvier, the axon initial segment, and the synapse. In line with a role of CASPR2 in the mature nervous system, neurological autoimmune diseases have been described in patients without neurodevelopmental disorders but with antibodies directed against CASPR2. These autoimmune diseases were of two types: central with memory disorders and temporal lobe seizures, or peripheral with muscular hyperactivity. Overall, we review the up-to-date knowledge on CASPR2 function and pinpoint confused or lacking information that will need further investigation.

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Section: Caspr2 In Network Formationmentioning

confidence: 69%

Section: Structure Expression and Function Of Caspr2mentioning

confidence: 99%

Contactin‐associated protein‐like 2, a protein of the neurexin family involved in several human diseases

Saint‐Martin

Joubert

Pellier‐Monnin

et al. 2018

Eur J of Neuroscience

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“…Oligodendrocyte pathology is associated with decreased motor performance in humans and in mice (Kato et al, 2020;Mandolesi et al, 2019;Nomura et al, 2019). Changes in myelin itself can also correlate with altered behaviors (Franco-Pons et al, 2007;Scott et al, 2019). DTI and functional connectivity MRI (resting-state fMRI [rs-fMRI]) are used to assess structural integrity and functional connectivity in humans and rodents (Bergmann et al, 2016;Dodero et al, 2013;Grandjean et al, 2014a;Liska et al, 2015;Sforazzini et al, 2016;Zerbi et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Brain-wide structural and functional disruption in mice with oligodendrocyte specificNf1deletion is rescued by inhibition of NOS

Asleh

Shofty

Cohen

et al. 2020

Preprint

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Neurofibromin gene (NF1) mutation causes Neurofibromatosis type 1 (NF1), a disorder in which brain white matter deficits identified by neuroimaging are common, yet of unknown cellular etiology. In mice, Nf1 loss in adult oligodendrocyte causes myelin decompaction, and increases oligodendrocyte nitric oxide (NO) levels. Nitric oxide synthase (NOS) inhibitors rescue this pathology. Whether oligodendrocyte pathology is sufficient to affect brainwide structure and account for NF1 imaging findings is unknown. Here, we show that Nf1 gene inactivation in adult oligodendrocytes (Plp-Nf1 fl/+ mice) results in a motor coordination deficit. Magnetic resonance imaging in awake mice shows that fractional anisotropy is reduced in Plp-Nf1 fl/+ corpus callosum and that interhemispheric functional connectivity in motor cortex is also reduced, consistent with disrupted myelin integrity. Further, NOS-specific inhibition rescued both measures. These results demonstrate that oligodendrocyte defects account for aspects of brain dysfunction in NF1, which can be identified by neuroimaging and ameliorated by NOS inhibition. Significance statementThis study assesses the effects of myelin decompaction on motor behavior and brain-wide structural and functional connectivity, and the effect of nitric oxide synthase (NOS) inhibition by N-nitro-L-arginine methyl ester (L-NAME) on these imaging measures. We report that inducible oligodendrocyte-specific inactivation of the Nf1 gene, which causes myelin decompaction, results in reduced motor coordination. Using diffusion-based MRI we show reduced myelin integrity and using functional MRI we show reduced functional connectivity in awake passive mice. L-NAME administration results in rescue of the pathology at the mesoscopic level using imaging procedures that can be directly applied to humans to study treatment efficacy in clinical trials.

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“…Cntnap2 knockout neurons showed impaired axonal growth and synaptic abnormalities, which might play important roles in autism [Canali et al, 2018;Spooren, Lindemann, Ghosh, & Santarelli, 2012;Varea et al, 2015]. Moreover, disruption of Cntnap2 in mice showed stereotypic behaviors as well as communication and social abnormalities, which are the core symptoms of autism [Brumback et al, 2018;Penagarikano et al, 2011;Scott et al, 2019]. Thus, CNTNAP2 was considered as one of the most high-risk genes for ASD.…”

Section: Introductionmentioning

confidence: 99%

Association between CNTNAP2 polymorphisms and autism: A family‐based study in the chinese han population and a meta‐analysis combined with GWAS data of psychiatric genomics consortium

Zhang

Wang

et al. 2019

Autism Research

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Autism is a childhood neuropsychiatric disorder with evidence of a strong genetic component in the complex etiologies. Contactin‐associated protein‐like 2 (CNTNAP2), a member of the neurexin superfamily, plays an essential role in neural development. CNTNAP2 was considered as one of the most susceptible genes for autism spectrum disorder (ASD). Some studies indicated the association of CNTNAP2 with ASD, while others reported no association. Given the inconsistent results of the previous studies, we performed a family‐based association study between 9 single‐nucleotide polymorphisms (SNPs) of CNTNAP2 and autism in 640 autistic trios in the Chinese Han population. Then, an updated meta‐analysis, combined with the data from Psychiatric Genomics Consortium (iPSYCH‐PGC ASD, 2017) and available association studies, was conducted. No SNPs were significantly associated with autism in the Chinese Han population. In the meta‐analysis, the two frequently reported SNPs (rs2710102 and rs7794745) showed no significant association with ASD. Therefore, CNTNAP2 polymorphisms might not be associated with autism. Autism Research 2019, 12: 553–561. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary In present family‐based association study, no single‐nucleotide polymorphisms (SNPs) were significantly associated with autism in the Chinese Han population. In the updated meta‐analysis, the association between the two frequently reported SNPs (rs2710102 and rs7794745) in CNTNAP2 and the risk of ASD was explored. However, the results showed no significant association. Therefore, our study suggested that CNTNAP2 polymorphisms might not be associated with autism.

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Loss ofCntnap2Causes Axonal Excitability Deficits, Developmental Delay in Cortical Myelination, and Abnormal Stereotyped Motor Behavior

Cited by 78 publications

References 64 publications

Contactin‐associated protein‐like 2, a protein of the neurexin family involved in several human diseases

Contactin‐associated protein‐like 2, a protein of the neurexin family involved in several human diseases

Brain-wide structural and functional disruption in mice with oligodendrocyte specificNf1deletion is rescued by inhibition of NOS

Association between CNTNAP2 polymorphisms and autism: A family‐based study in the chinese han population and a meta‐analysis combined with GWAS data of psychiatric genomics consortium

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