ArticleMolecular therapy : the journal of the American Society of Gene Therapy2021
Restoring neuronal chloride homeostasis with anti-NKCC1 gene therapy rescues cognitive deficits in a mouse model of Down syndrome.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 31 citations in OpenAlex.
- Trial
- Gliomas phenocopy an inborn error of metabolism to drive neuronal activity and tumor growth.Cell · 2026Article
- Medical treatment of autism spectrum disorder in children: Current evidence, controversies, and clinical challenges.World journal of clinical pediatrics · 2026Article
- miRNAs mediated Hsa21 gene suppression as potential therapeutic agent for Down syndrome: molecular dynamics and MM/PBSA-based study.Journal of molecular modeling · 2026Article
- Chloride Homeostasis in Neuronal Disorders: Bridging Measurement to Therapy.Life (Basel, Switzerland) · 2025Review
- NKCC1 inhibition improves sleep quality and EEG information content in a Down syndrome mouse model.iScience · 2025Article
- The NKCC1 Inhibitor Bumetanide Restores Cortical Feedforward Inhibition and Lessens Sensory Hypersensitivity in Early Postnatal Fragile X Mice.Biological psychiatry · 2025Article
- Infantile Spasms in Pediatric Down Syndrome: Potential Mechanisms Driving Therapeutic Considerations.Children (Basel, Switzerland) · 2024Review
- Adeno-associated virus vector delivery to the brain: Technology advancements and clinical applications.Advanced drug delivery reviews · 2024Review
- Heterogeneous subpopulations of GABAiScience · 2024Article
- Article
- Understanding the genetic mechanisms and cognitive impairments in Down syndrome: towards a holistic approach.Journal of neurology · 2024Review
- Pharmacology of Compounds Targeting Cation-Chloride Cotransporter Physiology.Handbook of experimental pharmacology · 2024Article
- Integration of ATAC-seq and RNA-seq identifies MX1-mediated AP-1 transcriptional regulation as a therapeutic target for Down syndrome.Biological research · 2023Article
- Imbalanced expression of cation-chloride cotransporters as a potential therapeutic target in an Angelman syndrome mouse model.Scientific reports · 2023Article
- LSD1/PRMT6-targeting gene therapy to attenuate androgen receptor toxic gain-of-function ameliorates spinobulbar muscular atrophy phenotypes in flies and mice.Nature communications · 2023Article
- Cation-Chloride Cotransporters KCC2 and NKCC1 as Therapeutic Targets in Neurological and Neuropsychiatric Disorders.Molecules (Basel, Switzerland) · 2023Review
- Severe inflammation in new-borns induces long-term cognitive impairment by activation of IL-1β/KCC2 signaling during early development.BMC medicine · 2022Article
- Sexually dimorphic DYRK1A overexpression on postnatal day 15 in the Ts65Dn mouse model of Down syndrome: Effects of pharmacological targeting on behavioral phenotypes.Pharmacology, biochemistry, and behavior · 2022Article
- How Staying Negative Is Good for the (Adult) Brain: Maintaining Chloride Homeostasis and the GABA-Shift in Neurological Disorders.Frontiers in molecular neuroscience · 2022Review
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Authors and funding
13 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.