α2‐glycine receptors modulate adult hippocampal neurogenesis and spatial memory

Abstract

The α2-glycine receptors (GlyRs) play important roles during early central nervous system development. However, these receptors' possible involvement in neurodevelopmental events occurring in the adult brain remains to be explored. Adult hippocampal neurogenesis (AHN) is the process by which new granule cell neurons are added to the dentate gyrus (DG) throughout adulthood. In this study, we observed that hippocampal adult neural stem cells (ANSCs) express α2-containing GlyRs. Pharmacological inhibition of GlyRs by strychnine or picrotoxin decreased the proliferation of ANSCs, both in vivo and in vitro. Mice knockout for glra2, the gene coding for the GlyR α2 subunit, were determined to display impaired AHN, and this phenomenon was accompanied by deficits in spatial memory. These results, which reveal neurodevelopmental roles for α2-GlyRs in the adult brain, may be clinically relevant, given that a mutation in GLAR2, as well as AHN impairments, have been reported in autism spectrum disorder. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 1430-1441, 2017.

Ethanol consumption and sedation are altered in mice lacking the glycine receptor α2 subunit

“…Open‐field assays did not show differences between genotypes in total distance travelled or time spent in the centre, which is in agreement with previously published data (Blednov et al, 2015; Lin et al, 2017;Molchanova et al, 2018 ; Pilorge et al, 2016). However, we detected changes in motor learning skills using the accelerating rotarod that showed an increased latency to fall in both male and female Glra2 KO mice.…”

“…Alteration in glutamatergic transmission, cortical synaptic plasticity (Morelli et al, 2017) and impaired motor memory consolidation were also detected in this mouse (Molchanova et al, 2018) suggesting the presence of compensatory mechanisms. On the other hand, using another model of Glra2 KO mice, it was shown that this mouse displayed impaired adult hippocampal neurogenesis and deficits in spatial memory (Lin et al, 2017).…”

“…These results suggest that Glra2 KO mice would need more conditioning sessions to show preference for the ethanol side compared to WT mice. Alternatively, it is possible that because the KO mice have shown memory deficits (Lin et al, 2017; Pilorge et al, 2016), they might not be able to recall the side with the positive reinforcement. The results obtained in conditioned place preference and drinking in the dark demonstrated important differences in motivation and preference for ethanol in the Glra2 KO mice that might be explained due to the absence of α2 subunits or compensatory effects that may occur in the KO animal.…”

In trans variant calling reveals enrichment for compound heterozygous variants in genes involved in neuronal development and growth.

“…In another report, deletions including DIP2C and/or ZMYND11 were identified in several patients with developmental delay including three patients with seizures (DeScipio et al, 2012). GLRA2 is a glycine receptor involved in neurodevelopment in which mutations are implicated in autism, (Pilorge et al, 2016;Lin et al, 2017) including a patient with comorbid epilepsy (Zhang et al, 2017).…”

In trans variant calling reveals enrichment for compound heterozygous variants in genes involved in neuronal development and growth.

“…In another report, deletions including DIP2C and/or ZMYND11 were identified in several patients with developmental delay including three patients with seizures (DeScipio et al, 2012). GLRA2 is a glycine receptor involved in neurodevelopment in which variants are implicated in autism (Pilorge et al, 2016;Lin et al, 2017), including a patient with comorbid epilepsy (Zhang et al, 2017).…”