Glutamate Dehydrogenase-Deficient Mice: A Novel Mouse Model of Schizophrenia-Like Phenotypes

Background: Glutamatergic abnormalities are commonly observed in schizophrenia (SZ), but all current medications for SZ symptoms target monoaminergic neurotransmitter systems, and are inefficient in treating all symptom clusters. Animal models that capture glutamatergic abnormalities in SZ and mimic its behavioral and neurochemical attributes are critical for better understanding of the neurobiology of the disorder and for the development of new pharmacological treatments. Recent findings indicate that expression of glutamate dehydrogenase (Glud1) mRNA is reduced in the hippocampus of patients with SZ, particularly in the CA1 subregion. Glud1 encodes the GDH protein, a mitochondrial enzyme that converts glutamate to alpha-ketoglutarate. Aim: To assess whether a CNS-specific deletion of Glud1 in nestin-cre::GLUD1 lox/+ (CNS-GLUD1+/−) mice or nestin-cre::GLUD1 lox/lox (CNS-GLUD1−/−) mice leads to abnormal glutamate levels, abnormal hippocampal physiology or gene expression, or behavioral alterations relevant to SZ psychopathology.

Methods: Hippocampal samples from Glud1-deficient mice were analyzed for glutamate levels and for mRNA gene expression of excitatory (glutamatergic) and inhibitory (GABAergic) markers. Extracellular recordings from hippocampal slices were also performed. Male and female CNS-Glud1 deficient (CNS-Glud1+/− and CNS-Glud1−/−) and control (CNS-Glud1+/+) mice were tested in adulthood for behavioral deficits using assays of positive-like, negative-like or cognitive symptoms. We assessed Gene x Environment effects on behavior by subjecting all genotypes to group housing or social isolation (SI) conditions starting in mid-adolescence.

Results: CNS-Glud1-deficient mice show elevated glutamate levels in the right hippocampus, and elevated expression of excitatory and inhibitory markers in dorsal, but not ventral, CA1. CNS-Glud1-/- mice also show enhanced amplitude of mEPSCs in Schaffer collateral neurons. Behaviorally, CNS-Glud1−/− mice exhibit impaired nesting behavior, baseline and amphetamine-induced hyperactivity in the open field and deficits in reversal learning and extra-dimensional set shifting. Whereas group-housed CNS-Glud1+/− mice lacked a behavioral phenotype, social Isolation in adolescence triggered reversal and extra-dimensional set shifting deficits in these heterozygotes.

Conclusion: Collectively, these studies show that Glud1 deficiency in CNS phenocopies key features of SZ in mice. Thus, Glud1 may play a critical role in SZ-related pathology, and moreover, glutamate metabolism in the hippocampus may drive SZ-related pathology. These findings could lead to better understanding of SZ etiology and provide new treatment venues for its symptoms.