Hippocampal long-term synaptic depression and memory deficits induced in early amyloidopathy are prevented by enhancing G-protein-gated inwardly rectifying potassium channel activity.

Autor: Sánchez-Rodríguez I; NeuroPhysiology & Behavior Laboratory, Centro Regional de Investigaciones Biomédicas, School of Medicine of Ciudad Real, University of Castilla-La Mancha, Ciudad Real, Spain., Djebari S; NeuroPhysiology & Behavior Laboratory, Centro Regional de Investigaciones Biomédicas, School of Medicine of Ciudad Real, University of Castilla-La Mancha, Ciudad Real, Spain., Temprano-Carazo S; NeuroPhysiology & Behavior Laboratory, Centro Regional de Investigaciones Biomédicas, School of Medicine of Ciudad Real, University of Castilla-La Mancha, Ciudad Real, Spain., Vega-Avelaira D; Departamento de Ciencias Biomédicas Básicas, European University of Madrid, Madrid, Spain., Jiménez-Herrera R; NeuroPhysiology & Behavior Laboratory, Centro Regional de Investigaciones Biomédicas, School of Medicine of Ciudad Real, University of Castilla-La Mancha, Ciudad Real, Spain., Iborra-Lázaro G; NeuroPhysiology & Behavior Laboratory, Centro Regional de Investigaciones Biomédicas, School of Medicine of Ciudad Real, University of Castilla-La Mancha, Ciudad Real, Spain., Yajeya J; Instituto de Neurociencias de Castilla y León, University of Salamanca, Salamanca, Spain., Jiménez-Díaz L; NeuroPhysiology & Behavior Laboratory, Centro Regional de Investigaciones Biomédicas, School of Medicine of Ciudad Real, University of Castilla-La Mancha, Ciudad Real, Spain., Navarro-López JD; NeuroPhysiology & Behavior Laboratory, Centro Regional de Investigaciones Biomédicas, School of Medicine of Ciudad Real, University of Castilla-La Mancha, Ciudad Real, Spain.
Jazyk: angličtina
Zdroj: Journal of neurochemistry [J Neurochem] 2020 May; Vol. 153 (3), pp. 362-376. Date of Electronic Publication: 2020 Jan 30.
DOI: 10.1111/jnc.14946
Abstrakt: Hippocampal synaptic plasticity disruption by amyloid-β (Aβ) peptides + thought to be responsible for learning and memory impairments in Alzheimer's disease (AD) early stage. Failures in neuronal excitability maintenance seems to be an underlying mechanism. G-protein-gated inwardly rectifying potassium (GirK) channels control neural excitability by hyperpolarization in response to many G-protein-coupled receptors activation. Here, in early in vitro and in vivo amyloidosis mouse models, we study whether GirK channels take part of the hippocampal synaptic plasticity impairments generated by Aβ 1-42 . In vitro electrophysiological recordings from slices showed that Aβ 1-42 alters synaptic plasticity by switching high-frequency stimulation (HFS) induced long-term potentiation (LTP) to long-term depression (LTD), which led to in vivo hippocampal-dependent memory deficits. Remarkably, selective pharmacological activation of GirK channels with ML297 rescued both HFS-induced LTP and habituation memory from Aβ 1-42 action. Moreover, when GirK channels were specifically blocked by Tertiapin-Q, their activation with ML297 failed to rescue LTP from the HFS-dependent LTD induced by Aβ 1-42 . On the other hand, the molecular analysis of the recorded slices by western blot showed that the expression of GIRK1/2 subunits, which form the prototypical GirK channel in the hippocampus, was not significantly regulated by Aβ 1-42 . However, immunohistochemical examination of our in vivo amyloidosis model showed Aβ 1-42 to down-regulate hippocampal GIRK1 subunit expression. Together, our results describe an Aβ-mediated deleterious synaptic mechanism that modifies the induction threshold for hippocampal LTP/LTD and underlies memory alterations observed in amyloidosis models. In this scenario, GirK activation assures memory formation by preventing the transformation of HFS-induced LTP into LTD.
(© 2019 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)
Databáze: MEDLINE
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