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

Kfir Asraf, Hiba Zaidan, Baylasan Natoor, Inna Gaisler-Salomon

Research output: Contribution to journalArticlepeer-review

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.

Original languageAmerican English
Article number248
JournalTranslational Psychiatry
Volume13
Issue number1
DOIs
StatePublished - 7 Jul 2023

All Science Journal Classification (ASJC) codes

  • Psychiatry and Mental health
  • Biological Psychiatry
  • Cellular and Molecular Neuroscience

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