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 clozapine-like 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.
Bibliographical noteFunding Information:
We thank Shonagh O’Leary Moore for help with the MRS tissue analysis, Kenneth Hess and Fan Hau for mouse imaging, Karin Krueger, Sara Steinfeld and Alexei Chemia-kine for expert performance of the surgical procedures and neurochemical analyses for the microdialysis studies, and Xiaoqiao Zhu for assisting with behavioral studies. We are grateful to Ina Weiner for critical discussion. The behavioral experiments utilized the facilities of the Rodent Models Neurobehavioral Analysis Core of the Lieber Center for Schizophrenia Research at Columbia University and the New York State Psychiatric Institute (Holly M. Moore, Director). This work was supported by the NIMH (P50 MH066171 to SR and HM, R01 MH068073 to PB), NIDA (K02 DA000356 to SR, T32 DA016224 to IGS, R01 DA016373 to MPG), NIA (R01 AG025161 to SAS), NINDS (R01 NS049442 to OA), the Joe Young Sr. Research Fund in Psychiatry (MPG), the Wayne State Anesthesiology Research Fund (MPG), and the Rothschild Foundation (IGS).
ASJC Scopus subject areas
- Psychiatry and Mental health