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Brain imaging has revealed that the CA1 subregion of the hippocampus is hyperactive in prodromal and diagnosed patients with schizophrenia (SCZ), and that glutamate is a driver of this hyperactivity. Strikingly, mice deficient in the glutamate synthetic enzyme glutaminase have CA1 hypoactivity and a SCZ-resilience profile, implicating glutamate-metabolizing enzymes. To address this further, we examined mice with a brain-wide deficit in the glutamate-metabolizing enzyme glutamate dehydrogenase (GDH), encoded by Glud1, which should lead to glutamate excess due to reduced glutamate metabolism in astrocytes. We found that Glud1-deficient mice have behavioral abnormalities in the 3 SCZ symptom domains, with increased baseline and amphetamine-induced hyperlocomotion as a positive symptom proxy, nest building and social preference as a negative symptom proxy, and reversal/extradimensional set shifting in the water T-maze and contextual fear conditioning as a cognitive symptom proxy. Neuroimaging of cerebral blood volume revealed hippocampal hyperactivity in CA1, which was associated with volume reduction. Parameters of hippocampal synaptic function revealed excess glutamate release and an elevated excitatory/inhibitory balance in CA1. Finally, in a direct clinical correlation using imaging-guided microarray, we found a significant SCZ-associated postmortem reduction in GLUD1 expression in CA1. These findings advance GLUD1 deficiency as a driver of excess hippocampal excitatory transmission and SCZ symptoms, and identify GDH as a target for glutamate modulation pharmacotherapy for SCZ. More broadly, these findings point to the likely involvement of alterations in glutamate metabolism in the pathophysiology of SCZ.

Background Glutamatergic abnormalities are commonly observed in schizophrenia (SZ) and are hypothesized to play an important role in cognitive dysfunction. While the contribution of postsynaptic glutamate receptors to SZ psychopathology has been extensively examined, less is known about the role played by enzymes involved in glutamate metabolism and homeostasis. We examined mice with a brain-wide deficit in the glutamate metabolizing enzyme glutamate dehydrogenase (GDH), encoded by Glud1, which leads to glutamate excess due to reduced glutamate metabolism in astrocytes. Methods We investigated astrocytic and neuronal abnormalities in mice with a CNS-specific mutation in Glud1. We asked whether CNS-Glud1 deficient mice would display behavioral abnormalities in a battery of tests that assess different aspects of schizophrenia-like psychopathology. We further asked whether an environmental manipulation, i.e. stress exposure, would exacerbate the behavioral abnormalities and astrocytic-neuronal gene expression patterns in heterozygous and homozygous mice. Results We found that mice with a homozygous mutation in CNS-Glud1, with a primarily astrocytic deficit in glutamate metabolism, display enhanced glutamate levels, an elevated excitatory/inhibitory balance in CA1, and abnormally high mRNA expression of neuronal and astrocytic markers of glutamate transmission specifically in dorsal CA1. Homozygous Glud1-deficient mice also showed several behavioral abnormalities, e.g. amphetamine-induced hyperlocomotion, nest building and social preference deficits, and abnormal reversal/extradimensional set shifting in the water T-maze. While heterozygous mice displayed no major behavioral or molecular abnormalities, their exposure to stress led to cognitive dysfunction; this gene x environment interaction may be mediated by disrupted function of the neuron-glia interface. Conclusions Collectively, these studies show that GDH-mediated glutamate metabolism in astrocytes impacts on neuronal glutamate transmission and release. GDH disruption, also demonstrated in post-mortem CA1 of patients with SZ, leads to SZ-like deficits in mice. GDH disruption and exposure to stress may cumulatively disrupt neuronal-astrocytic communication. These findings could lead to better understanding of the glutamate tripartite synapse and its contribution to SZ-like etiology. [ABSTRACT FROM AUTHOR]