Glutaminase-Deficient Mice Display Hippocampal Hypoactivity, Insensitivity to Pro-Psychotic Drugs and Potentiated Latent Inhibition: Relevance to Schizophrenia

Abstract

Dysregulated glutamatergic neurotransmission has been strongly implicated in the pathophysiology of schizophrenia (SCZ).Recently, presynaptic modulation of glutamate transmission has been shown to have therapeutic promise. We asked whether genetic knockdown of glutaminase (gene GLS1) to reduce glutamatergic transmission presynaptically by slowing the recycling of glutamine to glutamate, would produce a phenotype relevant to SCZ and its treatment. GLS1 heterozygous (GLS1 het) mice showed about a 50% global reduction in glutaminase activity, and a modest reduction in glutamate levels in brain regions relevant to SCZ pathophysiology, but displayed neither general behavioral abnormalities nor SCZ-associated phenotypes. Functional imaging, measuring regional cerebral blood volume, showed hippocampal hypometabolism mainly in the CA1 subregion and subiculum, the inverse of recent clinical imaging findings in prodromal and SCZ patients. GLS1 het mice were less sensitive to the behavioral stimulating effects of amphetamine, showed a reduction in amphetamine-induced striatal dopamine release and in ketamine-induced frontal cortical activation, suggesting that GLS1 het mice are resistant to the effects of these pro-psychotic challenges. Moreover, GLS1 het mice showed clozapinelike potentiation of latent inhibition, suggesting that reduction in glutaminase has antipsychotic-like properties. These observations provide further support for the pivotal role of altered glutamatergic synaptic transmission in the pathophysiology of SCZ, and suggest that presynaptic modulation of the glutamine-glutamate pathway through glutaminase inhibition may provide a new direction for the pharmacotherapy of SCZ.

Glutaminase 1 Is Essential for the Differentiation, Proliferation, and Survival of Human Neural Progenitor Cells

“…Therefore, genetic, immunological, or pharmacological inhibition of GLS1 needs to be cautious on the potential complications. Furthermore, Gls1 KO mice died at postnatal day 1 due to glutamatergic synaptic transmission disruptions [26], and Gls1 + / -mice displayed deteriorated hippocampal activity and developed schizophrenia-like symptoms [34]. These studies on GLS1 knockout (Gls1 KO) mice are consistent with our evaluation of the critical role of GLS1 on neurogenesis, particularly on the formation of neuronal network.…”

Targeted inhibition of tumor-specific glutaminase diminishes cell-autonomous tumorigenesis

“…Hence, we crossed the LAP/MYC mice with Gls +/-heterozygotes, which were previously documented to have decreased GLS protein and enzymatic activity (44). These Gls +/-heterozygotes developed normally, with subtle neurological findings (44,45 ) animals. MYC expression was induced at 1 week postnatally by withdrawal of doxycycline.…”

Brain glutaminases

“…Therefore, they postulate that a reduction of Glu in hippocampus after GA inhibition could be an effective therapeutic strategy in schizophrenia. As a proof of principle, the researchers employed transgenic heterozygous mutant mice partially lacking the Gls gene and showing 50% global reduction in GA activity (110). The mice displayed hippocampal hypometabolism mainly in the CA1 region (the inverse pattern observed in schizophrenic patients) and were less sensitive to pro-psychotic drugs.…”