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Sci Rep. 2017 Nov 7;7(1):14658. doi: 10.1038/s41598-017-15306-8.

Activation of G-protein-gated inwardly rectifying potassium (Kir3/GirK) channels rescues hippocampal functions in a mouse model of early amyloid-β pathology.

Author information

1
University of Castilla-La Mancha, NeuroPhysiology & Behavior Laboratory, Centro Regional de Investigaciones Biomédicas, Albacete, Spain.
2
University of Salamanca, Instituto de Neurociencias de Castilla y León, Salamanca, Spain.
3
Pablo de Olavide University, Division of Neurosciences, Seville, Spain.
4
University of Castilla-La Mancha, NeuroPhysiology & Behavior Laboratory, Centro Regional de Investigaciones Biomédicas, Albacete, Spain. Lydia.Jimenez@uclm.es.
5
University of Castilla-La Mancha, NeuroPhysiology & Behavior Laboratory, Centro Regional de Investigaciones Biomédicas, Albacete, Spain. Juan.Navarro@uclm.es.

Abstract

The hippocampus plays a critical role in learning and memory. Its correct performance relies on excitatory/inhibitory synaptic transmission balance. In early stages of Alzheimer's disease (AD), neuronal hyperexcitability leads to network dysfunction observed in cortical regions such as the hippocampus. G-protein-gated potassium (GirK) channels induce neurons to hyperpolarize, contribute to the resting membrane potential and could compensate any excesses of excitation. Here, we have studied the relationship between GirK channels and hippocampal function in a mouse model of early AD pathology. Intracerebroventricular injections of amyloid-β (Aβ 1-42) peptide-which have a causal role in AD pathogenesis-were performed to evaluate CA3-CA1 hippocampal synapse functionality in behaving mice. Aβ increased the excitability of the CA3-CA1 synapse, impaired long-term potentiation (LTP) and hippocampal oscillatory activity, and induced deficits in novel object recognition (NOR) tests. Injection of ML297 alone, a selective GirK activator, was also translated in LTP and NOR deficits. However, increasing GirK activity rescued all hippocampal deficits induced by Aβ due to the restoration of excitability values in the CA3-CA1 synapse. Our results show a synaptic mechanism, through GirK channel modulation, for the prevention of the hyperexcitability that causally contributes to synaptic, network, and cognitive deficits found in early AD pathogenesis.

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