Early correction of synaptic long-term depression improves abnormal anxiety-like behavior in adult GluN2B-C456Y-mutant mice

Abstract

Extensive evidence links Glutamate receptor, ionotropic, NMDA2B (GRIN2B), encoding the GluN2B/NR2B subunit of N-methyl-D-aspartate receptors (NMDARs), with various neurodevelopmental disorders, including autism spectrum disorders (ASDs), but the underlying mechanisms remain unclear. In addition, it remains unknown whether mutations in GluN2B, which starts to be expressed early in development, induces early pathophysiology that can be corrected by early treatments for long-lasting effects. We generated and characterized Grin2b-mutant mice that carry a heterozygous, ASD-risk C456Y mutation (Grin2b +/C456Y). In Grin2b +/C456Y mice, GluN2B protein levels were strongly reduced in association with decreased hippocampal NMDAR currents and NMDAR-dependent long-term depression (LTD) but unaltered long-term potentiation, indicative of mutation-induced protein degradation and LTD sensitivity. Behaviorally, Grin2b +/C456Y mice showed normal social interaction but exhibited abnormal anxiolytic-like behavior. Importantly, early, but not late, treatment of young Grin2b +/C456Y mice with the NMDAR agonist D-cycloserine rescued NMDAR currents and LTD in juvenile mice and improved anxiolytic-like behavior in adult mice. Therefore, GluN2B-C456Y haploinsufficiency decreases GluN2B protein levels, NMDAR-dependent LTD, and anxiety-like behavior, and early activation of NMDAR function has long-lasting effects on adult mouse behavior.

Two de novo GluN2B mutations affect multiple NMDAR-functions and instigate severe pediatric encephalopathy

“…Lastly, the reductions in τ off due to overexpression of the variants strongly suggests that the remaining current is contributed by the faster deactivating GluN2A-subunits ( Figure 8d ; Paoletti et al, 2013 ). Notably, these effects are consistent with our dominant-negative observations (see Figure 4 ) and results obtained from animal model bearing a GluN2B LoF mutation ( Shin et al, 2020 ).…”

“…First, mutant receptors bearing two copies of the variants are (likely) completely non-functional physiologically. This can be potentially related to cases of haploinsufficiency (with 50% the amount of the protein [ García-Recio et al, 2021 ; Santos-Gómez et al, 2021 ; Shin et al, 2020 ]); however, the normal expression of the G689S variant challenges this categorization. Third, the variants instigate a strong dominant-negative effect over glutamate potency when combined with 2B wt subunits (see Discussion).…”

Application of a FL Time Series Building Model in Mobile Network Interaction Anomaly Detection in the Internet of Things Environment

“…Among various behaviors of mobile network interaction, it is vulnerable to diversified attacks. Once abnormal behaviors of mobile network interaction occur, they often cause many adverse effects on network devices [4][5][6]. In addition to the attacks on the network, there are also attacks on the devices of the Internet of ings [7].…”

Dendrites of Neocortical Pyramidal Neurons: The Key to Understand Intellectual Disability

“…A striking example is represented by the mutations of the NMDA receptor subunits, whose consequence is represented either by loss or by gain of function, with possible excitotoxic mechanisms mediating the damage in the latter case (Lemke et al 2016;Fry et al 2018). NMDA mutations can also result in modified synaptic plasticity (Shin et al 2020) and interference with dendritic growth (Sceniak et al 2019).…”