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© Uwe Maskos
Tranche d'hippocampe de souris colorée avec deux toxines spécifiques de sous-types de récepteur nicotinique, en rouge (grains), et en vert (corps cellulaires). L'hippocampe est la zone du cerveau qui gère la mémoire spatiale.
Publication : Molecular psychiatry

The alpha7 nicotinic acetylcholine receptor mediates network dysfunction in a mouse model of local amyloid pathology.

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in Molecular psychiatry - 23 Sep 2025

Koukouli F, Zhang CL, Lazarevich I, Rooy M, Lamotte d'Incamps B, Gaspar Santos D, Pons S, Peixoto J, Thiberge C, Nikolakopoulou I, Changeux JP, Bacci A, Gutkin BS, Schmidt-Hieber C, Maskos U

Link to Pubmed [PMID] – 40987885

Link to DOI – 10.1038/s41380-025-03241-4

Mol Psychiatry 2025 Sep; ():

Patient and animal model data suggest a link between the cholinergic neuromodulatory system and the amyloid beta (Aβ) peptide in causing Alzheimer’s disease (AD). But how cholinergic dysfunctions contribute to AD pathology remains controversial. In a mouse model of local amyloid pathology, we show that in the early disease stages, the α7 nicotinic acetylcholine receptor (nAChR) is an important target of Aβ in the prefrontal cortex (PFC). Using in vivo two-photon calcium imaging and in vivo patch-clamp electrophysiology in the PFC of awake mice, we demonstrate that Aβ-mediated disruption of specifically the α7 nAChR subunit, expressed by distinct interneuron subtypes, results in substantial deficits in network activity. This is corroborated by electrophysiology experiments in slices. Combined with computational modeling, we propose that α7 nAChRs are occluded by Aβ early in the disease, whereas the heteropentameric α5 and β2 nAChRs are only partially inactivated and potentially provide novel therapeutic targets for intervention. Accordingly, we show that galantamine, an approved acetylcholine-esterase inhibitor (AChE-I), which acts as a positive allosteric modulator (PAM) of α5-containing nAChRs at low concentrations, reduces neuronal hyperactivity.