Restoring neuronal chloride homeostasis with anti-NKCC1 gene therapy rescues cognitive deficits in a mouse model of Down syndrome.

Molecular therapy : the journal of the American Society of Gene Therapy 2021 May 29

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A common feature of diverse brain disorders is the alteration of GABA-mediated inhibition because of aberrant, intracellular chloride homeostasis induced by changes in the expression and/or function of chloride transporters. Notably, pharmacological inhibition of the chloride importer NKCC1 is able to rescue brain-related core deficits in animal models of these pathologies and in some human clinical studies. Here, we show that reducing NKCC1 expression by RNA interference in the Ts65Dn mouse model of Down syndrome (DS) restores intracellular chloride concentration, efficacy of gamma-aminobutyric acid (GABA)-mediated inhibition, and neuronal network dynamics in vitro and ex vivo. Importantly, adeno-associated virus (AAV)-mediated, neuron-specific NKCC1 knockdown in vivo rescues cognitive deficits in diverse behavioral tasks in Ts65Dn animals. Our results highlight a mechanistic link between NKCC1 expression and behavioral abnormalities in DS mice and establish a molecular target for new therapeutic approaches, including gene therapy, to treat brain disorders characterized by neuronal chloride imbalance. Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Citation

Martina Parrini, Shovan Naskar, Micol Alberti, Ilaria Colombi, Giovanni Morelli, Anna Rocchi, Marina Nanni, Federica Piccardi, Severine Charles, Giuseppe Ronzitti, Federico Mingozzi, Andrea Contestabile, Laura Cancedda. Restoring neuronal chloride homeostasis with anti-NKCC1 gene therapy rescues cognitive deficits in a mouse model of Down syndrome. Molecular therapy : the journal of the American Society of Gene Therapy. 2021 May 29;29(10):3072-3092