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Cnksr2 Loss in Mice Leads to Increased Neural Activity and Behavioral Phenotypes of Epilepsy-Aphasia Syndrome.

Publication ,  Journal Article
Erata, E; Gao, Y; Purkey, AM; Soderblom, EJ; McNamara, JO; Soderling, SH
Published in: J Neurosci
November 17, 2021

Epilepsy Aphasia Syndromes (EAS) are a spectrum of childhood epileptic, cognitive, and language disorders of unknown etiology. CNKSR2 is a strong X-linked candidate gene implicated in EAS; however, there have been no studies of genetic models to dissect how its absence may lead to EAS. Here we develop a novel Cnksr2 KO mouse line and show that male mice exhibit increased neural activity and have spontaneous electrographic seizures. Cnksr2 KO mice also display significantly increased anxiety, impaired learning and memory, and a progressive and dramatic loss of ultrasonic vocalizations. We find that Cnksr2 is expressed in cortical, striatal, and cerebellar regions and is localized at both excitatory and inhibitory postsynapses. Proteomics analysis reveals Cnksr2 anchors key binding partners at synapses, and its loss results in significant alterations of the synaptic proteome, including proteins implicated in epilepsy disorders. Our results validate that loss of CNKSR2 leads to EAS and highlights the roles of Cnksr2 in synaptic organization and neuronal network activity.SIGNIFICANCE STATEMENT Epilepsy Aphasia Syndromes (EAS) are at the severe end of a spectrum of cognitive-behavioral symptoms seen in childhood epilepsies, and they remain an inadequately understood disorder. The prognosis of EAS is frequently poor, and patients have life-long language and cognitive disturbances. Here we describe a genetic mouse model of EAS, based on the KO of the EAS risk gene Cnksr2 We show that these mice exhibit electrophysiological and behavioral phenotypes similar to those of patients, providing an important new model for future studies of EAS. We also provide insights into the molecular disturbances downstream of Cnksr2 loss by using in vivo quantitative proteomics tools.

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Published In

J Neurosci

DOI

EISSN

1529-2401

Publication Date

November 17, 2021

Volume

41

Issue

46

Start / End Page

9633 / 9649

Location

United States

Related Subject Headings

  • Syndrome
  • Phenotype
  • Neurology & Neurosurgery
  • Nerve Tissue Proteins
  • Mice, Knockout
  • Mice
  • Landau-Kleffner Syndrome
  • Disease Models, Animal
  • Behavior, Animal
  • Animals
 

Citation

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Erata, E., Gao, Y., Purkey, A. M., Soderblom, E. J., McNamara, J. O., & Soderling, S. H. (2021). Cnksr2 Loss in Mice Leads to Increased Neural Activity and Behavioral Phenotypes of Epilepsy-Aphasia Syndrome. J Neurosci, 41(46), 9633–9649. https://doi.org/10.1523/JNEUROSCI.0650-21.2021
Erata, Eda, Yudong Gao, Alicia M. Purkey, Erik J. Soderblom, James O. McNamara, and Scott H. Soderling. “Cnksr2 Loss in Mice Leads to Increased Neural Activity and Behavioral Phenotypes of Epilepsy-Aphasia Syndrome.J Neurosci 41, no. 46 (November 17, 2021): 9633–49. https://doi.org/10.1523/JNEUROSCI.0650-21.2021.
Erata E, Gao Y, Purkey AM, Soderblom EJ, McNamara JO, Soderling SH. Cnksr2 Loss in Mice Leads to Increased Neural Activity and Behavioral Phenotypes of Epilepsy-Aphasia Syndrome. J Neurosci. 2021 Nov 17;41(46):9633–49.
Erata, Eda, et al. “Cnksr2 Loss in Mice Leads to Increased Neural Activity and Behavioral Phenotypes of Epilepsy-Aphasia Syndrome.J Neurosci, vol. 41, no. 46, Nov. 2021, pp. 9633–49. Pubmed, doi:10.1523/JNEUROSCI.0650-21.2021.
Erata E, Gao Y, Purkey AM, Soderblom EJ, McNamara JO, Soderling SH. Cnksr2 Loss in Mice Leads to Increased Neural Activity and Behavioral Phenotypes of Epilepsy-Aphasia Syndrome. J Neurosci. 2021 Nov 17;41(46):9633–9649.

Published In

J Neurosci

DOI

EISSN

1529-2401

Publication Date

November 17, 2021

Volume

41

Issue

46

Start / End Page

9633 / 9649

Location

United States

Related Subject Headings

  • Syndrome
  • Phenotype
  • Neurology & Neurosurgery
  • Nerve Tissue Proteins
  • Mice, Knockout
  • Mice
  • Landau-Kleffner Syndrome
  • Disease Models, Animal
  • Behavior, Animal
  • Animals