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Inhibition of parvalbumin-expressing interneurons results in complex behavioral changes
J A Brown1,2, T S Ramikie1,3, M J Schmidt1,3
1Department of Psychiatry, Psychiatry and Kennedy Center, Vanderbilt University, Nashville, TN, USA.
Molecular Psychiatry
|January 28, 2015
Summary
Reduced glutamic acid decarboxylase (GAD67) in parvalbumin-positive (PVALB+) cells impairs GABAergic transmission. This leads to sensorimotor gating deficits, altered novelty seeking, and reduced fear extinction in mice, mirroring schizophrenia phenotypes.
Area of Science:
- Neuroscience
- Molecular Biology
- Psychiatry
Background:
- Reduced expression of glutamic acid decarboxylase (GAD67) is a key feature of schizophrenia.
- GAD67 downregulation affects various interneurons, including parvalbumin-positive (PVALB+) cells.
Purpose of the Study:
- To investigate the role of PVALB+ GABAergic interneurons in behavior and molecular processes.
- To model schizophrenia-related deficits by specifically reducing GAD67 in PVALB+ cells.
Main Methods:
- Generated transgenic mice with Gad1 transcript knockdown specifically in PVALB+ cells using a microRNA targeting Gad1 mRNA.
- Verified construct expression via immunohistochemistry.
- Conducted electrophysiological studies and behavioral characterization, including sensorimotor gating, novelty seeking, and fear extinction tests.
Main Results:
- Electrophysiology showed reduced GABA release probability in prefrontal cortex pyramidal neurons.
- Transgenic mice exhibited significant sensorimotor gating deficits, increased novelty seeking, and reduced fear extinction.
- Ketamine's N-methyl-d-aspartate (NMDA) receptor antagonism showed opposing dose-dependent effects on behavior.
Conclusions:
- Reduction of GABAergic transmission from PVALB+ interneurons significantly impacts fear and novelty-seeking behaviors.
- These findings suggest a link between PVALB+ interneuron dysfunction and the behavioral phenotype observed in schizophrenia.
