GABAergic interneuron origin of schizophrenia pathophysiology
Kazu Nakazawa1, Veronika Zsiros, Zhihong Jiang
1Unit on Genetics of Cognition and Behavior, National Institute of Mental Health, Department of Health and Human Services, Bethesda, MD 20892, USA. nakazawk@mail.nih.gov
Neuropharmacology
|February 1, 2011
Summary
N-methyl-d-aspartic acid receptor (NMDAR) hypofunction in GABAergic interneurons causes schizophrenia-like symptoms. Disruptions in these fast-spiking neurons may underlie schizophrenia by impairing cortical circuit control and synchronization.
Area of Science:
- Neuroscience
- Psychiatry
- Molecular Biology
Background:
- N-methyl-d-aspartic acid receptor (NMDAR) hypofunction is linked to schizophrenia-like symptoms.
- The specific brain regions and cell types mediating these effects are not well understood.
- The GABAergic origin hypothesis suggests NMDAR hypofunction in GABAergic interneurons is key.
Purpose of the Study:
- To investigate the role of NMDAR hypofunction in cortical and hippocampal GABAergic interneurons in schizophrenia-like phenotypes.
- To test the hypothesis that NMDAR hypofunction specifically in parvalbumin (PV)-positive interneurons is sufficient to induce these symptoms.
Main Methods:
- Generation of transgenic mice with selective NMDAR deletion in cortical and hippocampal GABAergic interneurons (primarily PV-positive).
- Comprehensive assessment of molecular, physiological, and behavioral phenotypes in these mice.
- Review of existing literature on GABAergic interneuron dysfunction in schizophrenia.
Main Results:
- Selective NMDAR deletion in GABAergic interneurons triggered phenotypes resembling human schizophrenia.
- PV-positive, fast-spiking interneurons were identified as critical for these effects.
- These interneurons are crucial for temporal control of cortical inhibition and gamma-band oscillations.
Conclusions:
- NMDAR hypofunction in cortical, PV-positive, fast-spiking interneurons during development likely produces schizophrenia-like effects.
- Disruption of these interneurons impairs control and synchronization of cortical circuits, potentially causing schizophrenia symptoms.
- Vulnerability of these interneurons to genetic and environmental factors may explain their role in schizophrenia development.
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