Hippocampal long-term synaptic depression and memory deficits induced in early amyloidopathy are prevented by enhancing G-protein-gated inwardly rectifying potassium channel activity.
J Neurochem
; 153(3): 362-376, 2020 05.
Article
em En
| MEDLINE
| ID: mdl-31875959
ABSTRACT
Hippocampal synaptic plasticity disruption by amyloid-ß (Aß) 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 Aß1-42 . In vitro electrophysiological recordings from slices showed that Aß1-42 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 Aß1-42 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 Aß1-42 . 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 Aß1-42 . However, immunohistochemical examination of our in vivo amyloidosis model showed Aß1-42 to down-regulate hippocampal GIRK1 subunit expression. Together, our results describe an Aß-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.
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Base de dados:
MEDLINE
Assunto principal:
Potenciais Pós-Sinápticos Excitadores
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Depressão Sináptica de Longo Prazo
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Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G
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Hipocampo
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Amiloidose
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Transtornos da Memória
Limite:
Animals
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article