Mouse<i>Cntnap2</i>and Human<i>CNTNAP2</i>ASD Alleles Cell Autonomously Regulate PV+ Cortical Interneurons

Vogt, Daniel; Cho, Kathleen K.A.; Shelton, Samantha M; Paul, Anirban; Huang, Z. Josh; Sohal, Vikaas S.; Rubenstein, John L.R.

doi:10.1093/cercor/bhx248

Cited by 79 publications

(96 citation statements)

References 66 publications

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“…Notably, as reported previously, WT mice transplanted with medial ganglionic eminence (MGE)-derived interneurons isolated from Cntnap2 KO mice, presented a reduced number of PV+ interneurons (Vogt et al, 2017). This phenotype was rescued by Cntnap2 gene transduction into KO MGE interneurons but not by 4 Cntnap2 missense mutants (N407S, N418D, G731S, and T1278I), which could act as null/hypomorphic alleles.…”

Section: Pathological Modelssupporting

confidence: 70%

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: Pathological Modelssupporting

confidence: 70%

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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“…Growing evidence supports a fundamental role of fast-spiking parvalbumin (PV) GABAergic interneurons in maintaining the E:I balance by acting as an essential regulator of synchronized activity (Packer and Yuste, 2011). Further, their function is heavily diminished in numerous psychiatric diseases, including schizophrenia and autism and their expression is reduced in many relevant animal models including CNTNAP2, FMR1, En2 and Shank3 knock-out mice (Penagarikano et al, 2011, Vogt et al, 2017, Wohr et al, 2015. This results in over-excitation of neocortex, which has been associated with spontaneous recurrent seizures, hyperactivity and impaired neural signaling (Penagarikano et al, 2011, Ajram et al, 2017.…”

Section: Introductionmentioning

confidence: 99%

Cortical excitation:inhibition imbalance causes abnormal brain network dynamics as observed in neurodevelopmental disorders

Markicevic

Fulcher

Lewis

et al. 2018

Preprint

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AbstractAbnormal brain development manifests itself at different spatial scales. However, whether abnormalities at the cellular level can be diagnosed from network activity measured withfunctional magnetic resonance imaging (fMRI) is largely unknown, yet of high clinical relevance. Here we applied fMRI while using chemogenetics to increase the excitation-to-inhibition ratio (E:I) within cortical microcircuits of the mouse brain, thereby mimicking a putative mechanism of neurodevelopmental disorders including autism. Increased E:I caused a significant reduction of long-range connectivity, irrespective of whether excitatory neurons were facilitated or inhibitory Parvalbumin interneurons were suppressed. Training a classifier on fMRI signals, we were able to accurately classify cortical areas exhibiting increased E:I. This classifier was validated in an independent cohort of Fmr1y/- knock-out mice, a model for autism with well-documented loss of Parvalbumin neurons and chronic alterations of E:I. Our findings demonstrate a promising novel approach towards inferring microcircuit abnormalities from macroscopic fMRI measurements.

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“…The development of PV cell circuit connectivity is a prolonged process, terminating around the end of adolescence in rodents and primates , Chattopadhyaya et al, 2007, Baho et al, 2019, Baho and Di Cristo, 2012, Fish et al, 2013. PV cells dysfunction has been found in several mouse models of autism (Selimbeyoglu et al, 2017, Mierau et al, 2016, Chao et al, 2010, Patrizi et al, 2019, Vogt et al, 2018. Conversely, stimulating PV cells has been shown to be sufficient to ameliorate social behaviour (Yizhar et al, 2011, Cao et al, 2018b, Selimbeyoglu et al, 2017.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of mTOR during a postnatal critical sensitive window rescues deficits in GABAergic PV cell connectivity and social behavior caused by loss ofTSC1

Choudhury

Amegandjin

Jadhav

et al. 2020

Preprint

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Mutations in regulators of the Mechanistic Target Of Rapamycin Complex 1 (mTORC1), such as Tsc1/2, lead to neurodevelopmental disorders associated with autism, intellectual disabilities and epilepsy. Whereas the effects of mTORC1 signaling dysfunction within diverse cell types are likely critical for the onset of the diverse neurological symptoms associated with mutations in mTORC1 regulators, they are not well understood. In particular, the effects of mTORC1 dys-regulation in specific types of inhibitory interneurons are unclear.Here, we showed that Tsc1 haploinsufficiency in parvalbumin (PV)-positive GABAergic interneurons either in cortical organotypic cultures or in vivo caused a premature increase in their perisomatic innervations, followed by a striking loss in adult mice. This effects were accompanied by alterations of AMPK-dependent autophagy in pre-adolescent but not adult mice. PV cell-restricted Tsc1 mutant mice showed deficits in social behavior. Treatment with the mTOR inhibitor Rapamycin restricted to the third postnatal week was sufficient to permanently rescue deficits in both PV cell innervation and social behavior in adult conditional haploinsufficient mice. All together, these findings identify a novel role of Tsc1-mTORC1 signaling in the regulation of the developmental time course and maintenance of cortical PV cell connectivity and provide a mechanistic basis for the targeted rescue of autism-related behaviors in disorders associated with deregulated mTORC1 signaling.

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MouseCntnap2and HumanCNTNAP2ASD Alleles Cell Autonomously Regulate PV+ Cortical Interneurons

Cited by 79 publications

References 66 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

Cortical excitation:inhibition imbalance causes abnormal brain network dynamics as observed in neurodevelopmental disorders

Inhibition of mTOR during a postnatal critical sensitive window rescues deficits in GABAergic PV cell connectivity and social behavior caused by loss ofTSC1

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