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

Epilepsy Aphasia Syndromes (EAS) are a spectrum of childhood epileptic, cognitive, and language disorders of unknown etiology. 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 no...

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Bibliographic Details
Published in:The Journal of neuroscience 2021-11, Vol.41 (46), p.9633-9649
Main Authors: Erata, Eda, Gao, Yudong, Purkey, Alicia M, Soderblom, Erik J, McNamara, James O, Soderling, Scott H
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - deficiency
Animals
Aphasia
Behavior, Animal
Cerebellum
Children
Cognitive ability
Disease Models, Animal
Disorders
Epilepsy
Etiology
Landau-Kleffner Syndrome
Mice
Mice, Knockout
Neostriatum
Nerve Tissue Proteins - deficiency
Neural networks
Phenotype
Phenotypes
Proteomes
Proteomics
Seizures
Synapses
Syndrome
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Summary:Epilepsy Aphasia Syndromes (EAS) are a spectrum of childhood epileptic, cognitive, and language disorders of unknown etiology. 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 KO mouse line and show that male mice exhibit increased neural activity and have spontaneous electrographic seizures. 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. 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 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 quantitative proteomics tools.
ISSN:0270-6474
1529-2401
DOI:10.1523/jneurosci.0650-21.2021