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

Lydia Jiménez‐Díaz,David Vega‐Avelaira,Javier Yajeya,Juan D Navarro‐López,Raquel Jiménez‐Herrera,Sara Temprano‐Carazo,Souhail Djebari,Guillermo Iborra‐Lázaro,Irene Sánchez‐Rodríguez

doi:10.1111/jnc.14946

Abstract

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 Aβ1–42. In vitro electrophysiological recordings from slices showed that Aβ1–42 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 Aβ1–42 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 Aβ1–42. 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 Aβ1–42. However, immunohistochemical examination of our in vivo amyloidosis model showed Aβ1–42 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.

Highlights

One important mechanism controlling the excess of excitation in neurons relies on G-protein-gated inwardly rectifying potassium (Kir3/G-protein-gated inwardly rectifying potassium channels (GirK)) channels
It is well stablished that high-frequency stimulation (HFS) applied to the Schaffer collaterals induces long-term potentiation (LTP) of the synaptic responses (Bliss, Collingridge, Morris, & Reymann, 2018) but in the present work we show that Aβ transforms HFS-induced LTP into long-term depression (LTD) with subsequent memory formation impairment
C, HFS induced LTD, with similar values to Aβ1–42 or TQ + Aβ1–42 groups, but significantly different to control slices. These results indicate that GirK channels blocking by TQ did not interfere with Aβ1–42 action but avoided the ML297 conservative effects on LTP mechanisms in our in vitro model of amyloidosis

Summary

| INTRODUCTION

One important mechanism controlling the excess of excitation in neurons relies on G-protein-gated inwardly rectifying potassium (Kir3/GirK) channels. It is well stablished that high-frequency stimulation (HFS) applied to the Schaffer collaterals induces LTP of the synaptic responses (Bliss, Collingridge, Morris, & Reymann, 2018) but in the present work we show that Aβ transforms HFS-induced LTP into LTD with subsequent memory formation impairment This Aβ-deleterious action can be avoided by selective enhancement of GirK—dependent signaling supporting the hypothesis of counteracting neuronal hyperactivity as a potential tool to restore excitability levels and upstreaming functions lost in AD brain (Busche & Konnerth, 2015; Nava-Mesa, Jimenez-Diaz, Yajeya, & Navarro-Lopez, 2014; Palop & Mucke, 2016; Styr & Slutsky, 2018)

| MATERIALS AND METHODS

Findings

| DISCUSSION

| CONCLUSIONS