Impaired hippocampal plasticity associated with loss of recycling endosomal SLC9A6/NHE6 is ameliorated by the TrkB agonist 7,8-dihydroxyflavone.

Autor: Gao AYL; Department of Pharmacology & Therapeutics, McGill University, Montreal, Canada., Inglebert Y; Department of Pharmacology & Therapeutics, McGill University, Montreal, Canada., Shi R; Department of Pharmacology & Therapeutics, McGill University, Montreal, Canada., Ilie A; Department of Physiology, McGill University, Montreal, Canada., Popic J; Department of Biochemistry, McGill University, Montreal, Canada., Mustian J; Department of Pharmacology & Therapeutics, McGill University, Montreal, Canada., Sonenberg N; Department of Biochemistry, McGill University, Montreal, Canada., Orlowski J; Department of Physiology, McGill University, Montreal, Canada., McKinney RA; Department of Pharmacology & Therapeutics, McGill University, Montreal, Canada. Electronic address: anne.mckinney@mcgill.ca.
Jazyk: angličtina
Zdroj: Biochimica et biophysica acta. Molecular basis of disease [Biochim Biophys Acta Mol Basis Dis] 2025 Jan; Vol. 1871 (1), pp. 167529. Date of Electronic Publication: 2024 Sep 27.
DOI: 10.1016/j.bbadis.2024.167529
Abstrakt: Proper maintenance of intracellular vesicular pH is essential for cargo trafficking during synaptic function and plasticity. Mutations in the SLC9A6 gene encoding the recycling endosomal pH regulator (Na + , K + )/H + exchanger isoform 6 (NHE6) are causal for Christianson syndrome (CS), a severe form of X-linked intellectual disability. NHE6 expression is also downregulated in other neurodevelopmental and neurodegenerative disorders, such as autism spectrum disorder and Alzheimer's disease, suggesting its dysfunction could contribute more broadly to the pathophysiology of other neurological conditions. To understand how ablation of NHE6 function leads to severe learning impairments, we assessed synaptic structure, function, and cellular mechanisms of learning in a novel line of Nhe6 knockout (KO) mice expressing a plasma membrane-tethered green fluorescent protein within hippocampal neurons. We uncovered significant reductions in dendritic spines density, AMPA receptor (AMPAR) expression, and AMPAR-mediated neurotransmission in CA1 pyramidal neurons. The neurons also failed to undergo functional and structural enhancement during long-term potentiation (LTP). Significantly, the selective TrkB agonist 7,8-dihydroxyflavone restored spine density as well as functional and structural LTP in KO neurons. TrkB activation thus may act as a potential clinical intervention to ameliorate cognitive deficits in CS and other neurodegenerative disorders.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Crown Copyright © 2024. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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