THE IMPACT OF EARLY LIFE STRESS ON SCHIZOPHRENIA-LIKE COGNITIVE DEFICITS IN MICE HETEROZYGOUS FOR A MUTATION IN GLUTAMATE DEHYDROGENASE: A GENE X ENVIRONMENT MODEL

Schizophrenia (SZ) is associated with glutamate dysfunction, and its development is influenced by exposure to early life stress (ELS), which is a strong predictor of lifetime mental health. Glutamate dehydrogenase 1 (GDH/Glud1) is crucial for glutamate metabolism, and altered GDH mRNA expression has been identified in SZ. Previous studies show that CNS-Glud1-deficient mice exposed to mild early adult stress exhibit SZ-like behavioral abnormalities and aberrant mRNA expression patterns in the medial prefrontal cortex (mPFC).
Here, we investigated the impact of ELS on SZ-like behavioral deficits in heterozygous CNS-Glud1+/- mice and CNS-Cre+ controls using a novel overshadowing (OS( task, which measures salience attribution, a cognitive capacity associated with psychotic symptoms and linked to disrupted dopamine (DA) transmission in the mesolimbic pathway. We then measured mRNA expression of glutamate and dopamine markers the mPFC and Nucleus Accumbens (NAc).
Methods: ELS was induced using a limited bedding and nesting paradigm (PND 3-9). Adult mice were behaviorally tested (PND70-90), and mRNA expression changes were analyzed at two developmental timepoints (adolescence and adulthood) using RT-PCR. It was hypothesized that ELS-exposed CNS-Glud1+/- mice would display overshadowing deficits and molecular abnormalities, which would be evident in adulthood, but not in adolescence.
Our preliminary results demonstrate a gene X environment interaction, with ELS and Glud1 heterozygosity resulting in aberrant overshadowing and altered marker expression in mPFC and NAc.
These findings contribute to our knowledge of how ELS interacts with deficits in glutamate transmission to produce attentional and molecular deficits.