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Silencing KCC2 in mouse dorsal hippocampus compromises spatial and contextual memory

Neuropsychopharmacology volume 48, pages 1067–1077 (2023)Cite this article

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Abstract

Delayed upregulation of the neuronal chloride extruder KCC2 underlies the progressive shift in GABA signaling polarity during development. Conversely, KCC2 downregulation is observed in a variety of neurological and psychiatric disorders often associated with cognitive impairment. Reduced KCC2 expression and function in mature networks may disrupt GABA signaling and promote anomalous network activities underlying these disorders. However, the causal link between KCC2 downregulation, altered brain rhythmogenesis, and cognitive function remains elusive. Here, by combining behavioral exploration with in vivo electrophysiology we assessed the impact of chronic KCC2 downregulation in mouse dorsal hippocampus and showed it compromises both spatial and contextual memory. This was associated with altered hippocampal rhythmogenesis and neuronal hyperexcitability, with increased burst firing in CA1 neurons during non-REM sleep. Reducing neuronal excitability with terbinafine, a specific Task-3 leak potassium channel opener, occluded the impairment of contextual memory upon KCC2 knockdown. Our results establish a causal relationship between KCC2 expression and cognitive performance and suggest that non-epileptiform rhythmopathies and neuronal hyperexcitability are central to the deficits caused by KCC2 downregulation in the adult mouse brain.

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Fig. 1: KCC2 down-regulation in dorsal hippocampus impairs spatial and contextual memory.
Fig. 2: KCC2 down-regulation in principal cells is sufficient to alter contextual memory.
Fig. 3: KCC2 downregulation leads to hippocampal network hyperexcitability.
Fig. 4: Task-3 channel activator terbinafine occludes memory deficits upon KCC2 knockdown.

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Acknowledgements

We thank Liset M de la Prida and Gabrielle Girardeau for helpful discussions and critical reading of the manuscript. We acknowledge the Imaging Platform of Institut du Fer à Moulin, where confocal imaging was performed and Atlantic Gene Therapy (UMR-1089, Univ. of Nantes) for AAV production, and the IBPS Phenotypic Core Facility where most behavioral tests were performed.

Funding

This work was supported in part by Fondation pour la Recherche Médicale (DEQ20140329539 to JCP), ERANET-Neuron (ACRoBAT project, funded by Agence Nationale de la Recherche to JCP), and the Fondation Française pour la Recherche sur l’Epilepsie—Fédération pour la Recherche sur le Cerveau (to JCP). C.S. and M.G. were recipients of fellowships from Sorbonne University and C.S. was partly supported by the Bio-Psy Laboratory of Excellence. The Poncer and Daumas labs are affiliated with the Bio-Psy Laboratory of Excellence, and DIM C-BRAINS funded by the Conseil Régional d’Ile-de-France.

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  1. Clémence Simonnet

    Present address: Basic Neuroscience Department, Centre Medical Universitaire, 1211, Geneva, Switzerland

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  1. Inserm UMR-S 1270, 75005, Paris, France

    Clémence Simonnet, Manisha Sinha, Marie Goutierre, Imane Moutkine & Jean Christophe Poncer

  2. Sorbonne Université, 75005, Paris, France

    Clémence Simonnet, Manisha Sinha, Marie Goutierre, Imane Moutkine, Stéphanie Daumas & Jean Christophe Poncer

  3. Institut du Fer à Moulin, 75005, Paris, France

    Clémence Simonnet, Manisha Sinha, Marie Goutierre, Imane Moutkine & Jean Christophe Poncer

  4. Neuroscience Paris Seine-Institut de Biologie Paris Seine (NPS-IBPS), 75005, Paris, France

    Stéphanie Daumas

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Contributions

CS, SD, and JCP designed the research; CS and MS performed the experiments; CS, MS, and MG analyzed the data; MS and MG wrote the MATLAB codes for data analysis; IM designed vectors for virus production; SD and JCP supervised the research; CS and JCP prepared the figures and wrote the manuscript with inputs from M.S., M.G. and S.D.

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Correspondence to Jean Christophe Poncer.

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Simonnet, C., Sinha, M., Goutierre, M. et al. Silencing KCC2 in mouse dorsal hippocampus compromises spatial and contextual memory. Neuropsychopharmacol. 48, 1067–1077 (2023). https://doi.org/10.1038/s41386-022-01480-5

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