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Int J Mol Sci. 2019 Mar 7;20(5). pii: E1168. doi: 10.3390/ijms20051168.

Role of GirK Channels in Long-Term Potentiation of Synaptic Inhibition in an In Vivo Mouse Model of Early Amyloid-β Pathology.

Author information

1
Neurophysiology & Behavior Laboratory, Centro Regional de Investigaciones Biomédicas, School of Medicine of Ciudad Real, University of Castilla-La Mancha, 13071 Ciudad Real, Spain. irene.sanchez@uclm.es.
2
Division of Neurosciences, University Pablo de Olavide, 41013 Seville, Spain. agrumas@upo.es.
3
Division of Neurosciences, University Pablo de Olavide, 41013 Seville, Spain. jmdelgar@uclm.es.
4
Neurophysiology & Behavior Laboratory, Centro Regional de Investigaciones Biomédicas, School of Medicine of Ciudad Real, University of Castilla-La Mancha, 13071 Ciudad Real, Spain. Lydia.Jimenez@uclm.es.
5
Neurophysiology & Behavior Laboratory, Centro Regional de Investigaciones Biomédicas, School of Medicine of Ciudad Real, University of Castilla-La Mancha, 13071 Ciudad Real, Spain. Juan.Navarro@uclm.es.

Abstract

Imbalances of excitatory/inhibitory synaptic transmission occur early in the pathogenesis of Alzheimer's disease (AD), leading to hippocampal hyperexcitability and causing synaptic, network, and cognitive dysfunctions. G-protein-gated potassium (GirK) channels play a key role in the control of neuronal excitability, contributing to inhibitory signaling. Here, we evaluate the relationship between GirK channel activity and inhibitory hippocampal functionality in vivo. In a non-transgenic mouse model of AD, field postsynaptic potentials (fPSPs) from the CA3⁻CA1 synapse in the dorsal hippocampus were recorded in freely moving mice. Intracerebroventricular (ICV) injections of amyloid-β (Aβ) or GirK channel modulators impaired ionotropic (GABAA-mediated fPSPs) and metabotropic (GirK-mediated fPSPs) inhibitory signaling and disrupted the potentiation of synaptic inhibition. However, the activation of GirK channels prevented Aβ-induced changes in GABAA components. Our data shows, for the first time, the presence of long-term potentiation (LTP) for both the GABAA and GirK-mediated inhibitory postsynaptic responses in vivo. In addition, our results support the importance of an accurate level of GirK-dependent signaling for dorsal hippocampal performance in early amyloid pathology models by controlling the excess of excitation that disrupts synaptic plasticity processes.

KEYWORDS:

Aβ1–42; GirK channels; fIPSP; freely moving mice; hippocampus; in vivo; inhibitory LTP; neuronal excitability; synaptic plasticity

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