ArticleNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology2009
Glutaminase-deficient mice display hippocampal hypoactivity, insensitivity to pro-psychotic drugs and potentiated latent inhibition: relevance to schizophrenia.
Article in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers, 1 of them a synthesis that pooled it.
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Who cites it
51 citing papers in PubMed, 1 synthesis or guideline pooled it, 87 citations in OpenAlex.
- Glutamate in schizophrenia: a focused review and meta-analysis of ¹H-MRS studies.Schizophrenia bulletin · 2013Pooled it
- The Role of GABA Pathway Components in Pathogenesis of Neurodevelopmental Disorders.International journal of molecular sciences · 2025Review
- The Glutamate/GABA-Glutamine Cycle: Insights, Updates, and Advances.Journal of neurochemistry · 2025Review
- Glutaminase - A potential target for cancer treatment.BioMedicine · 2024Review
- Novel Approaches to the Establishment of Local Microenvironment from Resorbable Biomaterials in the Brain In Vitro Models.International journal of molecular sciences · 2023Review
- Synergistic, long-term effects of glutamate dehydrogenase 1 deficiency and mild stress on cognitive function and mPFC gene and miRNA expression.Translational psychiatry · 2023Article
- Glial Glutamine Homeostasis in Health and Disease.Neurochemical research · 2023Review
- Beyond NMDA Receptors: Homeostasis at the Glutamate Tripartite Synapse and Its Contributions to Cognitive Dysfunction in Schizophrenia.International journal of molecular sciences · 2022Review
- Negative valence of hallucinatory voices as predictor of cortical glutamatergic metabolite levels in schizophrenia patients.Brain and behavior · 2022Article
- Enantiomers of 2-methylglutamate and 2-methylglutamine selectively impact mouse brain metabolism and behavior.Scientific reports · 2021Article
- Glutamate homeostasis and dopamine signaling: Implications for psychostimulant addiction behavior.Neurochemistry international · 2021Review
- Hippocampal Transcriptome-Wide Association Study Reveals Correlations Between Impaired Glutamatergic Synapse Pathway and Age-Related Hearing Loss in BXD-Recombinant Inbred Mice.Frontiers in neuroscience · 2021Article
- Dopamine Neurons That Cotransmit Glutamate, From Synapses to Circuits to Behavior.Frontiers in neural circuits · 2021Review
- Neurocircuitry of Reward and Addiction: Potential Impact of Dopamine-Glutamate Co-release as Future Target in Substance Use Disorder.Journal of clinical medicine · 2019Review
- Glutaminase activity in GLS1 Het mouse brain compared to putative pharmacological inhibition by ebselen using ex vivo MRS.Neurochemistry international · 2019Article
- Glutaminase Deficiency Caused by Short Tandem Repeat Expansion inThe New England journal of medicine · 2019Article
- JHU-083 selectively blocks glutaminase activity in brain CD11bNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2019Article
- Molecular Imaging of mGluR5 Availability with [Cellular and molecular neurobiology · 2019Article
- Glutamate Dehydrogenase-Deficient Mice Display Schizophrenia-Like Behavioral Abnormalities and CA1-Specific Hippocampal Dysfunction.Schizophrenia bulletin · 2019Article
- Hippocampal dysfunction in the pathophysiology of schizophrenia: a selective review and hypothesis for early detection and intervention.Molecular psychiatry · 2018Review
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Authors and funding
18 authors at 5 institutions in 2 countries.
Funding
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 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.
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