Reduction in the neuronal surface of post and presynaptic GABA B receptors in the hippocampus in a mouse model of Alzheimer's disease

Brain Pathol. 2020 May;30(3):554-575. doi: 10.1111/bpa.12802. Epub 2019 Dec 12.

Abstract

The hippocampus plays key roles in learning and memory and is a main target of Alzheimer's disease (AD), which causes progressive memory impairments. Despite numerous investigations about the processes required for the normal hippocampal functions, the neurotransmitter receptors involved in the synaptic deficits by which AD disables the hippocampus are not yet characterized. By combining histoblots, western blots, immunohistochemistry and high-resolution immunoelectron microscopic methods for GABAB receptors, this study provides a quantitative description of the expression and the subcellular localization of GABAB1 in the hippocampus in a mouse model of AD at 1, 6 and 12 months of age. Western blots and histoblots showed that the total amount of protein and the laminar expression pattern of GABAB1 were similar in APP/PS1 mice and in age-matched wild-type mice. In contrast, immunoelectron microscopic techniques showed that the subcellular localization of GABAB1 subunit did not change significantly in APP/PS1 mice at 1 month of age, was significantly reduced in the stratum lacunosum-moleculare of CA1 pyramidal cells at 6 months of age and significantly reduced at the membrane surface of CA1 pyramidal cells at 12 months of age. This reduction of plasma membrane GABAB1 was paralleled by a significant increase of the subunit at the intracellular sites. We further observed a decrease of membrane-targeted GABAB receptors in axon terminals contacting CA1 pyramidal cells. Our data demonstrate compartment- and age-dependent reduction of plasma membrane-targeted GABAB receptors in the CA1 region of the hippocampus, suggesting that this decrease might be enough to alter the GABAB -mediated synaptic transmission taking place in AD.

Keywords: Alzheimer's disease; GABAB receptors; electron microscopy; freeze-fracture; hippocampus; immunohistochemistry; ion channels.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Cell Membrane / metabolism
  • Disease Models, Animal
  • Hippocampus / metabolism*
  • Hippocampus / pathology
  • Mice
  • Mice, Transgenic
  • Neurons / metabolism*
  • Neurons / pathology
  • Presenilin-1 / genetics
  • Presenilin-1 / metabolism
  • Receptors, GABA-B / metabolism*
  • Synapses / metabolism*
  • Synapses / pathology
  • Synaptic Transmission / physiology
  • gamma-Aminobutyric Acid / metabolism

Substances

  • Amyloid beta-Protein Precursor
  • Presenilin-1
  • Receptors, GABA-B
  • gamma-Aminobutyric Acid