The GluN2B-Trp373 NMDA Receptor Variant is Associated with Autism-, Epilepsy-Related Phenotypes and Reduces NMDA Receptor Currents in Rats.

Autism spectrum disorder (ASD) is a neurodevelopmental condition with core clinical features of abnormal communication, social interactions, atypical intelligence, and a higher risk of epilepsy. Prior work has suggested that de novo heterozygous mutations in the GRIN2B gene that encodes the GluN2B subunit of N-methyl-D-aspartic acid receptors are likely linked to ASD. However, whether GLuN2B-Trp373 mutation derived from autistic individuals causes ASD-like behavioral aberrations in rats remains to be determined. Here, through in utero electroporation and in vivo studies, we conducted a battery of tests to examine ASD-associated behaviors, cognitive impairments, and susceptibility to pentylenetetrazol-induced seizures. Whole-cell patch recording was utilized to determine whether the GluN2B-Trp373 mutation influences GluN2B-containing NMDA receptor currents in rats. Results show that, behaviorally, GLuN2B-Trp373 mutant rats exhibited core behavioral manifestations of ASD, such as social interaction deficits, increases in stereotyped behaviors and anxiety stereotyped/repetitive, impaired spatial memory, and enhanced risk of pentylenetetrazol-induced seizures, consistent with many of the hallmarks of low-functioning ASD in humans. Functionally, the GluN2B-Trp373 mutation results in reduced GluN2B surface protein expression together with decreased hippocampal NMDA receptor currents. Collectively, our findings highlight that GluN2B-Trp373 mutations can drive the manifestation of ASD-associated symptoms via the suppression of NMDA receptor currents.

Neural network correlates of high-altitude adaptive genetic variants in Tibetans: A pilot, exploratory study.

Although substantial progress has been made in the identification of genetic substrates underlying physiology, neuropsychology, and brain organization, the genotype-phenotype associations remain largely unknown in the context of high-altitude (HA) adaptation. Here, we related HA adaptive genetic variants in three gene loci (EGLN1, EPAS1, and PPARA) to interindividual variance in a set of physiological characteristics, neuropsychological tests, and topological attributes of large-scale structural and functional brain networks in 135 indigenous Tibetan highlanders. Analyses of individual HA adaptive single-nucleotide polymorphisms (SNPs) revealed that specific SNPs selectively modulated physiological characteristics (erythrocyte level, ratio between forced expiratory volume in the first second to forced vital capacity, arterial oxygen saturation, and heart rate) and structural network centrality (the left anterior orbital gyrus) with no effects on neuropsychology or functional brain networks. Further analyses of genetic adaptive scores, which summarized the overall degree of genetic adaptation to HA, revealed significant correlations only with structural brain networks with respect to local interconnectivity of the whole networks, intermodule communication between the right frontal and parietal module and the left occipital module, nodal centrality in several frontal regions, and connectivity strength of a subnetwork predominantly involving in intramodule edges in the right temporal and occipital module. Moreover, the associations were dependent on gene loci, weight types, or topological scales. Together, these findings shed new light on genotype-phenotype interactions under HA hypoxia and have important implications for developing new strategies to optimize organism and tissue responses to chronic hypoxia induced by extreme environments or diseases.

A model of synaptic plasticity: activation of mGluR I induced long-term theta oscillations in medial septal diagonal band of rat brain slice.

This study aimed to establish a model of synaptic plasticity by the activation of metabotropic glutamate receptor (mGluR) I in rat medial septal diagonal band (MSDB). Electrophysiological experiment was performed to record the theta frequency oscillation activities in rat MSDB slices. The data were recorded and analyzed with Spike 2 (CED, Cambridge, UK). Application of aminocyclopentane-1, 3-dicarboxylic acid (ACPD) to MSDB slices produced theta frequency oscillations (4-12 Hz) which persisted for hours after ACPD washout, suggesting the existence of a form of synaptic plasticity in long-term oscillations (LTOs). Addition of NMDA receptor antagonist AP5 (50 µM) caused no significant change in area power. In contrast, AMPA/Kainate receptor antagonist NBQX administration partially reduced the area power. Infusion of ZD7288, a hyperpolarization-activated channel (Ih) inhibitor, caused additional reduction to control level. Comparable effects were also observed with administration of DHPG (3, 5-dihydroxyphenylglycine) which also elicited LTOs. mGluR I activation induced theta oscillation and this activity maintained hours after drug washout. Both AMPA and hyperpolarization-activated channel make an essential contribution to LTO. Our study herein established a model of synaptic plasticity.