Density of GABAB Receptors Is Reduced in Granule Cells of the Hippocampus in a Mouse Model of Alzheimer's Disease.

Alejandro Martín-Belmonte,Ryuichi Shigemoto,Luis de la Ossa,Rafael Luján,Rocío Alfaro-Ruíz,Alain Buisson,Yugo Fukazawa,Ana Esther Moreno-Martínez,Carolina Aguado,José Martínez-Hernández

doi:10.3390/ijms21072459

Abstract

Metabotropic γ-aminobutyric acid (GABAB) receptors contribute to the control of network activity and information processing in hippocampal circuits by regulating neuronal excitability and synaptic transmission. The dysfunction in the dentate gyrus (DG) has been implicated in Alzheimer´s disease (AD). Given the involvement of GABAB receptors in AD, to determine their subcellular localisation and possible alteration in granule cells of the DG in a mouse model of AD at 12 months of age, we used high-resolution immunoelectron microscopic analysis. Immunohistochemistry at the light microscopic level showed that the regional and cellular expression pattern of GABAB1 was similar in an AD model mouse expressing mutated human amyloid precursor protein and presenilin1 (APP/PS1) and in age-matched wild type mice. High-resolution immunoelectron microscopy revealed a distance-dependent gradient of immunolabelling for GABAB receptors, increasing from proximal to distal dendrites in both wild type and APP/PS1 mice. However, the overall density of GABAB receptors at the neuronal surface of these postsynaptic compartments of granule cells was significantly reduced in APP/PS1 mice. Parallel to this reduction in surface receptors, we found a significant increase in GABAB1 at cytoplasmic sites. GABAB receptors were also detected at presynaptic sites in the molecular layer of the DG. We also found a decrease in plasma membrane GABAB receptors in axon terminals contacting dendritic spines of granule cells, which was more pronounced in the outer than in the inner molecular layer. Altogether, our data showing post- and presynaptic reduction in surface GABAB receptors in the DG suggest the alteration of the GABAB-mediated modulation of excitability and synaptic transmission in granule cells, which may contribute to the cognitive dysfunctions in the APP/PS1 model of AD.

Highlights

The dentate gyrus (DG) is an integral part of the hippocampal formation and play key roles in the formation of episodic memory, spatial memory and exploration of new environments [1]
DTGhegsreanule cellsreadt u1c2timonosnitnhpsoosftsaygnea.pWticeaandddpirteiosynnaallpytirceGvAeaBlAaBdreeccreepatosersilnikperlyescyonnatrpibtiucteGtAo BthAe Bpraethcoeplotgoyrsanind axon termmineamlsoryinimtphaeirmcoemntmdiessscurirbaeld/aisnsothceiaAtiPoPn/aPlS1inmpoudtesl oafnAdDt,hperoveindtionrghninewal ininsipguhttss,tobuontdhercsotanntdacting the pathological events taking place in the disease. granule cells in a segregated manner. These reductions in postsynaptic and presynaptic GABAB receptors likely contribute to the pathology and memory impairment described in the APP/PS1 model of Alzheimers disease (AD), providing new insights to understand the pathological events taking place in the disease
The inhibition of GABAB receptors improves learning and memory formation [37,38] and altered GABAB receptor function has been involved in AD pathogenesis [39]

Summary

Introduction

The dentate gyrus (DG) is an integral part of the hippocampal formation and play key roles in the formation of episodic memory, spatial memory and exploration of new environments [1]. The major input of the DG arises from entorhinal cortex layer II neurons through the perforant path, and the functional integrity of this connection is necessary to fulfil its function in memory formation and spatial navigation [3]. Dysfunction in this entorhinal cortex–dentate gyrus pathway has been implicated in pathological conditions like Alzheimers disease (AD), the most prevalent neurodegenerative disease in the elderly population. An impairment of adult neurogenesis has been reported in the DG in AD patients [11]

Methods

Results

Conclusion