To investigate gene x environment interactions in a mouse model of cognitive deficits, we examined the impact of mild stress in mice genetically modified to express deficient levels of glutamate dehydrogenase 1 (GDH). GDH (gene name: Glud1) plays a central role in glutamate metabolism and is downregulated in the hippocampus of patients with schizophrenia. Mice with a full deletion of Glud1 in CNS (C-Glud1-/- mice) previously showed abnormally high glutamate levels and a wide range of behavioral deficits. Here, we exposed heterozygous C-Glud1+/- mice and their C-Cre+ controls to mild stress in early adulthood. Stress-naïve mice of both genotypes were used as controls. Seven days later, mice were tested in a battery of behavioral tests assessing locomotor activity, social behavior and cognitive function. Fourteen days following behavior, medial prefrontal cortex samples were removed and analyzed for expression changes in transcriptome and select microRNA molecules using RNA-seq and RT-PCR, respectively. In a second cohort, brains were extracted immediately after the stress. Stress-exposed C-Glud1+/- mice showed novelty-induced hypo-locomotion and impaired spatial acquisition and reversal. Transcriptomic analyses revealed vast changes in glutamatergic, GABAergic and stress-related genes, which were unique to stress-exposed Glud1-deficient mice. These behavioral and molecular deficits were absent in stress-naïve CNS-Glud1+/- mice and in stress-exposed CNS-Cre+ controls. MiR203-5p emerged as a potential mechanism for the effect of stress exposure. Our findings indicate that CNS-Glud1+/- mice exposed to stress in early adulthood display cognitive deficits, as well as molecular abnormalities, which are also relevant to stress exposure and psychopathology.