Activation of G-protein-gated Inwardly Rectifying Potassium (Kir3/GirK) Channels Rescues Hippocampal Functions in a Mouse Model of Early amyloid-β Pathology

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / physiopathology*
  • Amyloid beta-Peptides / administration & dosage
  • Amyloid beta-Peptides / pharmacology
  • Animals
  • CA3 Region, Hippocampal / metabolism
  • CA3 Region, Hippocampal / physiopathology
  • Disease Models, Animal
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / drug effects
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / metabolism*
  • Hippocampus / metabolism
  • Hippocampus / physiopathology*
  • Injections, Intraventricular
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Peptide Fragments / administration & dosage
  • Peptide Fragments / pharmacology
  • Phenylurea Compounds / pharmacology
  • Pyrazoles / pharmacology

Substances

  • Amyloid beta-Peptides
  • CID 56642816
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels
  • Peptide Fragments
  • Phenylurea Compounds
  • Pyrazoles
  • amyloid beta-protein (1-42)