Age-Dependent Degeneration of Mature Dentate Gyrus Granule Cells Following NMDA Receptor Ablation

Yasuhito Watanabe,Hannah Monyer,Jakob Von Engelhardt,Rolf Sprengel,Michaela K Müller,Peter H Seeburg

doi:10.3389/fnmol.2015.00087

Abstract

N-methyl-D-aspartate receptors (NMDARs) in all hippocampal areas play an essential role in distinct processes of memory formation as well as in sustaining cell survival of postnatally generated neurons in the dentate gyrus (DG). In contrast to the beneficial effects, over-activation of NMDARs has been implicated in many acute and chronic neurological diseases, reason why therapeutic approaches and clinical trials involving receptor blockade have been envisaged for decades. Here we employed genetically engineered mice to study the long-term effect of NMDAR ablation on selective hippocampal neuronal populations. Ablation of either GluN1 or GluN2B causes degeneration of the DG. The neuronal demise affects mature neurons specifically in the dorsal DG and is NMDAR subunit-dependent. Most importantly, the degenerative process exacerbates with increasing age of the animals. These results lead us to conclude that mature granule cells in the dorsal DG undergo neurodegeneration following NMDAR ablation in aged mouse. Thus, caution needs to be exerted when considering long-term administration of NMDAR antagonists for therapeutic purposes.

Highlights

The dentate gyrus (DG) in the hippocampus has been the focus of numerous studies for two main reasons
The dorsal DG is involved in cognitive functions such as spatial memory, whilst the ventral DG supports brain functions related to stress, emotion, and affect
To directly test whether the observed degeneration of mature DG granule cells following GluN1 depletion is indicative of a specific DG granule cell vulnerability, we investigated the effect of N-methyl-D-aspartate receptors (NMDARs) depletion in genetically modified mice (Grin1 DG), in which the manipulation was restricted to the DG

Summary

Introduction

The dentate gyrus (DG) in the hippocampus has been the focus of numerous studies for two main reasons. All hippocampal subregions have been much investigated in the context of distinct forms of plasticity, learning, and memory (e.g., McHugh et al, 2007; Niewoehner et al, 2007; Gu et al, 2012; Nakashiba et al, 2012). The DG is one of the two principal neurogenic niches in the postnatal brain, and has been frequently studied in the context of neurogenesis (reviewed in Jessberger and Gage, 2014). The DG comprises a dorsal and a ventral part that can be distinguished on anatomical grounds, and based on distinct functions that the two areas support. The dorsal DG is involved in cognitive functions such as spatial memory, whilst the ventral DG supports brain functions related to stress, emotion, and affect (reviewed in Fanselow and Dong, 2010)

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