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ORIGINAL RESEARCH article

Front. Mol. Neurosci.
Sec. Brain Disease Mechanisms
Volume 17 - 2024 | doi: 10.3389/fnmol.2024.1483238
This article is part of the Research Topic Neurobiological underpinnings of neurodegenerative and neuropsychiatric disorders: from models to therapy View all 9 articles

Unraveling the Socio-Cognitive Consequences of KCC2 Disruption in Zebrafish: Implications for Neurodevelopmental Disorders and Therapeutic Interventions

Provisionally accepted
Mohammad Naderi Mohammad Naderi *Thi My Nhi Ngugen Thi My Nhi Ngugen Christopher Pompili Christopher Pompili Raymond Kwong Raymond Kwong
  • York University, Toronto, Ontario, Canada

The final, formatted version of the article will be published soon.

    During postnatal brain development, maintaining a delicate balance between excitation and inhibition (E/I) is essential for the precise formation of neuronal circuits. The K+/Cl-cotransporter 2 (KCC2) is instrumental in this process, and its dysregulation is implicated in various neurological disorders. This study utilized zebrafish (Danio rerio) to investigate the socio-cognitive consequences of KCC2 disruption. Through CRISPR-Cas9 technology, biallelic kcc2a knockout zebrafish larvae were generated, revealing behavioral abnormalities, including impaired social interactions and memory deficits. Molecular analyses unveiled alterations in key genes associated with the GABAergic and glutamatergic systems, potentially contributing to E/I imbalance. Additionally, KCC2 disruption influenced the expression of oxytocin and BDNF, crucial regulators of social behaviors, synaptic plasticity, and memory formation.The study also explored the therapeutic potential of KCC2 modulation using pharmaceuticals, showing the rescuing effects of CLP-290 and LIT-001 on social abnormalities. However, the selective impact of LIT-001 on social behaviors, not memory, highlights the complexity of neurobehavioral modulation. In summary, this study sheds light on the pivotal role of KCC2 in shaping socio-cognitive functions and suggests potential therapeutic avenues for KCC2related neurological disorders.

    Keywords: K + /Cl -cotransporter 2, Zebrafish (Danio rerio), Memory, Oxytocin, excitation inhibition balance

    Received: 19 Aug 2024; Accepted: 26 Sep 2024.

    Copyright: © 2024 Naderi, Ngugen, Pompili and Kwong. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Mohammad Naderi, York University, Toronto, M3J 1P3, Ontario, Canada

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