ArticleSchizophrenia bulletin2019
Glutamate Dehydrogenase-Deficient Mice Display Schizophrenia-Like Behavioral Abnormalities and CA1-Specific Hippocampal Dysfunction.
Article in Schizophrenia bulletin, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
23 citing papers in PubMed, 1 synthesis or guideline pooled it, 37 citations in OpenAlex.
- Hippocampal subfield volumes in mild cognitive impairment and alzheimer's disease: a systematic review and meta-analysis.Brain imaging and behavior · 2023Pooled it
- Effects of diazepam on hippocampal blood flow in people at clinical high risk for psychosis.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2024Trial
- MSK1 mediates BDNF-dependent MeCP2-S421 phosphorylation in postnatal striatal development and psychiatric-relevant behaviours.Molecular psychiatry · 2026Article
- Targeting beta-2 adrenergic receptor attenuates schizophrenia-like behavioral effects induced by ketamine in mice: cAMP/PKA/BDNF-PEA-3 and RIM-1α signaling pathways involvement.Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2026Article
- Constellations of Thought: Astrocytic Contributions to Cognition Across Rodent Models of Brain Dysfunction.Biomolecules · 2026Review
- Effects of troxerutin on schizophrenia-like behaviors and oxidative damage in mice.Current research in physiology · 2026Article
- Valence-Driven Cognitive Flexibility: Neurochemical and Circuit-Level Insights from Animal Models and Their Relevance to Schizophrenia.Biomolecules · 2025Review
- Pharmacological reduction of reverse-translated hippocampal hyperactivity in mouse: relevance for psychosis.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2025Article
- The Glutamate/GABA-Glutamine Cycle: Insights, Updates, and Advances.Journal of neurochemistry · 2025Review
- Brain and behavioural anomalies caused byLife science alliance · 2025Article
- The Janus face of antipsychotics in glial cells: Focus on glioprotection.Experimental biology and medicine (Maywood, N.J.) · 2023Review
- Epigenetic activation of secretory phenotypes in senescence by the FOXQ1-SIRT4-GDH signaling.Cell death & disease · 2023Article
- Synergistic, long-term effects of glutamate dehydrogenase 1 deficiency and mild stress on cognitive function and mPFC gene and miRNA expression.Translational psychiatry · 2023Article
- Advanced Biomarkers of Hepatotoxicity in Psychiatry: A Narrative Review and Recommendations for New Psychoactive Substances.International journal of molecular sciences · 2023Review
- Oxidative stress impairs cognitive function by affecting hippocampal fimbria volume in drug-naïve, first-episode schizophrenia.Frontiers in neuroscience · 2023Article
- Developmental dynamics of RNA translation in the human brain.Nature neuroscience · 2022Article
- Beyond NMDA Receptors: Homeostasis at the Glutamate Tripartite Synapse and Its Contributions to Cognitive Dysfunction in Schizophrenia.International journal of molecular sciences · 2022Review
- Chronic α1-Na/K-ATPase inhibition reverses the elongation of the axon initial segment of the hippocampal CA1 pyramidal neurons in Angelman syndrome model mice.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2021Article
- Electrophysiological Characterization of Regular and Burst Firing Pyramidal Neurons of the Dorsal Subiculum in an Angelman Syndrome Mouse Model.Frontiers in cellular neuroscience · 2021Article
- Decreased Plasma Levels of Growth Differentiation Factor 11 in Patients With Schizophrenia: Correlation With Psychopathology and Cognition.Frontiers in psychiatry · 2020Article
Corrections and comments
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Authors and funding
13 authors at 4 institutions in 2 countries.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.