Synergistic, long-term effects of glutamate dehydrogenase 1 deficiency and mild stress on cognitive function and mPFC gene and miRNA expression

Abstract

Glutamate abnormalities in the medial prefrontal cortex (mPFC) are associated with cognitive deficits. We previously showed that homozygous deletion of CNS glutamate dehydrogenase 1 (Glud1), a metabolic enzyme critical for glutamate metabolism, leads to schizophrenia-like behavioral abnormalities and increased mPFC glutamate; mice heterozygous for CNS Glud1 deletion (C-Glud1+/− mice) showed no cognitive or molecular abnormalities. Here, we examined the protracted behavioral and molecular effects of mild injection stress on C-Glud1+/− mice. We found spatial and reversal learning deficits, as well as large-scale mPFC transcriptional changes in pathways associated with glutamate and GABA signaling, in stress-exposed C-Glud1+/− mice, but not in their stress-naïve or C-Glud1+/+ littermates. These effects were observed several weeks following stress exposure, and the expression levels of specific glutamatergic and GABAergic genes differentiated between high and low reversal learning performance. An increase in miR203-5p expression immediately following stress may provide a translational regulatory mechanism to account for the delayed effect of stress exposure on cognitive function. Our findings show that chronic glutamate abnormalities interact with acute stress to induce cognitive deficits, and resonate with gene x environment theories of schizophrenia. Stress-exposed C-Glud1+/− mice may model a schizophrenia high-risk population, which is uniquely sensitive to stress-related ‘trigger’ events.

Establishment of a Mitochondrial Metabolism-Related Diagnostic Model in Schizophrenia Based on LASSO Algorithm

“…Research by Virmani et al [ 45 ] suggests that the activity of the CPT system (CPT1 and CPT2) is associated with Parkinson’s disease, Alzheimer’s disease, and schizophrenia, mainly related to changes in insulin balance in the brain. GLUD1 in the central nervous system is a crucial metabolic enzyme in glutamate metabolism and can lead to behavioral abnormalities and increased mPFC glutamate in schizophrenia patients [ 46 ]. Research by Yadav et al [ 47 ] found that the absence of GLUD1 leads to abnormal emotional and social behavior.…”

Transcriptome Dynamics in Mouse Amygdala under Acute and Chronic Stress Revealed by Thiol-labeled RNA Sequencing

“…3g). These genes include known stress-related genes such as Cldn11, Vamp1, Glud1 and Etnppl [44][45][46][47]. For all of the overlapped genes, fold change is bigger for SLAM-seq analysis than RNA-seq (Fig.…”