No evidence for cognitive decline or neurodegeneration in strain-matched Grin3a knockout mice.

N-methyl-D-aspartate (NMDA) receptor (NMDAR) dysregulation is thought to contribute to impaired cognition and neurodegeneration in a variety of brain disorders. In a recent article, Zhong et al. proposed that deficiency of the NMDAR subunit GluN3A may be a primary pathogenic factor in sporadic Alzheimer´s disease (AD) based on evidence for degenerative excitotoxicity and cognitive impairment in aging mice lacking GluN3A. Because the result appeared to be at odds with earlier work where genetic GluN3A deletion enhanced learning in younger mice, we have now compared wild-type and GluN3A knockout mice at later life stages using a congenic mouse strain. Rather than age-dependent cognitive decline or neurodegeneration, we find that the enhanced performance of young adult GluN3A knockouts in memory tasks persists during aging. In sum, our analysis does not support the hypothesis that GluN3A loss underlies cognitive impairment in AD..

Grey matter changes on brain MRI in subjective cognitive decline: a systematic review.

INTRODUCTION: People with subjective cognitive decline (SCD) report cognitive deterioration. However, their performance in neuropsychological evaluation falls within the normal range. The present study aims to analyse whether structural magnetic resonance imaging (MRI) reveals grey matter changes in the SCD population compared with healthy normal controls (HC). METHODS: Parallel systematic searches in PubMed and Web of Science databases were conducted, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Quality assessment was completed using the Newcastle-Ottawa Scale (NOS). RESULTS: Fifty-one MRI studies were included. Thirty-five studies used a region of interest (ROI) analysis, 15 used a voxel-based morphometry (VBM) analysis and 10 studies used a cortical thickness (CTh) analysis. Ten studies combined both, VBM or CTh analysis with ROI analysis. CONCLUSIONS: Medial temporal structures, like the hippocampus or the entorhinal cortex (EC), seemed to present grey matter reduction in SCD compared with HC, but the samples and results are heterogeneous. Larger sample sizes could help to better determine if these grey matter changes are consistent in SCD subjects.

Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly.

De novo protein synthesis is required for synapse modifications underlying stable memory encoding. Yet neurons are highly compartmentalized cells and how protein synthesis can be regulated at the synapse level is unknown. Here, we characterize neuronal signaling complexes formed by the postsynaptic scaffold GIT1, the mechanistic target of rapamycin (mTOR) kinase, and Raptor that couple synaptic stimuli to mTOR-dependent protein synthesis; and identify NMDA receptors containing GluN3A subunits as key negative regulators of GIT1 binding to mTOR. Disruption of GIT1/mTOR complexes by enhancing GluN3A expression or silencing GIT1 inhibits synaptic mTOR activation and restricts the mTOR-dependent translation of specific activity-regulated mRNAs. Conversely, GluN3A removal enables complex formation, potentiates mTOR-dependent protein synthesis, and facilitates the consolidation of associative and spatial memories in mice. The memory enhancement becomes evident with light or spaced training, can be achieved by selectively deleting GluN3A from excitatory neurons during adulthood, and does not compromise other aspects of cognition such as memory flexibility or extinction. Our findings provide mechanistic insight into synaptic translational control and reveal a potentially selective target for cognitive enhancement.