Pubmed du 28/12/25
1. Abdullah A, Liu X, Murari K, Yan J, Cheng N. Alterations in auditory midbrain processing is observed in both female and male mouse model of Fragile X Syndrome. Neuroscience. 2025.
Auditory hypersensitivity is a common phenotype in Fragile X Syndrome. Electrophysiology studies at the inferior colliculus of male FMR1-knockout (KO) mice previously demonstrated increased neuronal firing, suggesting that the inferior colliculus is involved in auditory hypersensitivity. Here, we further explored whether the central nucleus of the inferior colliculus (ICc) is involved in auditory hypersensitivity in both female and male KO mice. Tone-evoked in-vivo electrophysiology recordings from ICc neurons of anesthetized (ketamine/xylazine) KO mice at both postnatal day 20 (P20) and 30 (P30) demonstrated increased spikes compared to age- and sex-matched wild-type (WT) mice. Within the KO group, increased spikes were observed in females compared with male mice. Both female and male KO mice also displayed decreased minimum threshold and enhanced response duration at both ages. Additionally, female P30 KO mice displayed weaker inverse relationship between response latency and spike number compared to their WT counterparts. Regarding developmental changes, spike number decreased with maturation in both female and male KO mice. Response duration reduced with age in both sexes of both genotypes, while minimum threshold decreased in the male mice. Finally, we observed an age-related strengthening of the inverse relationship between response latency and magnitude only in the WT mice. Our findings indicate that the ICc display auditory processing deficits particularly in the female KO mice and in young animals highlighting the importance of including female subjects in future studies, and studying early development, which could be an ideal stage for interventions.
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2. Kubota M, Yoshihara Y, Uwatoko T, Shoji R, Near J, Dehghani M, Aoki YY, Urayama SI, Okada T, Murai T. Elevated brain glutamine levels in adults with autism spectrum disorder: A 7T MRS study. Mol Psychiatry. 2025.
Alterations in excitatory neurotransmitters, involving the glutamate (Glu) and glutamine (Gln) cycle, as well as inhibitory neurotransmission, GABA, are implicated in the pathophysiology of autism spectrum disorder (ASD). Although magnetic resonance spectroscopy (MRS) holds promise for assessing these metabolites, conventional 3 T MRI does not robustly measure them, leaving the neurochemical pathophysiology of ASD insufficiently understood. 7 T MRI enables reliable assessments of these neurometabolites by enhancing the signal-to-noise ratio and improving the spectral resolution, particularly in distinguishing neuroactive Glu from its metabolic precursor, Gln. The current 7 T MRS study has two primary objectives: first, to investigate neurometabolite levels in adults with ASD to elucidate its neurochemical pathophysiology, and second, to examine their association with symptoms of ASD. Thirty-three adults with ASD (mean age = 31 years) and 52 age-matched control adults were included. The neurometabolite levels of Glu, Gln, and GABA were assessed in the anterior cingulate cortex (ACC), thalamus, and right temporo-parietal junction (TPJ), with most quantifications passing quality checks. Analysis of covariance revealed significant effects of diagnosis on Gln in the thalamus (p = 0.008) and right TPJ (p = 0.006), indicating elevated Gln levels in these regions in the ASD group. Among social communication and restricted and repetitive behaviors, significant negative correlations were observed in the ASD group between Gln levels and sensory symptoms. These findings suggest that alterations in the excitatory neurotransmission regulation, presumably increased cycling of the Gln-Glu circuit, may underlie the pathophysiology of ASD.
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3. Sette C, Urbinati C, Lanzillotta C, Prestia F, Ciafardini L, Cosentino L, Pietraforte D, Quattrini MC, Perluigi M, Di Domenico F, De Filippis B. Systemic administration of the OGT inhibitor OSMI-1 normalizes hippocampal O-GlcNAcylation and improves recognition memory, redox balance, and brain mitochondrial homeostasis in a Rett syndrome mouse model. Free Radic Biol Med. 2025.
Protein O-GlcNAcylation (O-GlcNAc) is a nutrient-responsive posttranslational modification (PTM). Proper regulation of brain O-GlcNAc levels is essential for the coupling between metabolic homeostasis and neuronal function. Abnormal O-GlcNAc levels in the brain are associated with neurodevelopmental and neurodegenerative diseases related to defects in energy metabolism. We investigated the levels and regulation of protein O-GlcNAc modification and related pathways through gene and protein expression analysis in the hippocampus of two well-established murine models of Rett syndrome (RTT), a monogenic neurodevelopmental disorder with metabolic components and a primary cause of severe intellectual disability in females. Increased protein O-GlcNAc levels, due to changes in the molecular machinery that controls O-GlcNAc production, transfer, and removal, were observed in the hippocampus of the two RTT mouse models (MeCP2-BIRD and MeCP2-308 models). Remarkably, systemic administration of the OGT inhibitor OSMI-1 restored O-GlcNAc brain homeostasis and rescued brain mitochondrial defects and redox alterations in the RTT mouse hippocampus. The OSMI-1 treatment also induced a normalization of the cognitive performance of RTT mice in novel object recognition tests and reduced peripheral oxidative stress. These findings provide new evidence of an imbalance in nutrient-sensing O-GlcNAc in the RTT mouse hippocampus, suggesting that restoring brain O-GlcNAc homeostasis might represent a promising therapeutic approach for RTT.
