Abstract
The transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) is a master regulator of metabolism in peripheral tissues, and it has been proposed that PGC-1alpha plays a similar role in the brain. Recent evidence suggests that PGC-1alpha is concentrated in GABAergic interneurons, so we investigated whether male and female PGC-1alpha -/- mice exhibit abnormalities in interneuron gene expression and/or function. We found a striking reduction in the expression of the Ca(2+)-binding protein parvalbumin (PV), but not other GABAergic markers, throughout the cerebrum in PGC-1alpha +/- and -/- mice. Furthermore, PGC-1alpha overexpression in cell culture was sufficient to robustly induce PV expression. Consistent with a reduction in PV rather than a loss of PV-expressing interneurons, spontaneous synaptic inhibition was not altered in PGC-1alpha -/- mice. However, evoked synaptic responses displayed less paired-pulse depression and dramatic facilitation in response to repetitive stimulation at the gamma frequency. PV transcript expression was also significantly reduced in retina and heart of PGC-1alpha -/- animals, suggesting that PGC-1alpha is required for proper expression of PV in multiple tissues. Together these findings indicate that PGC-1alpha is a novel regulator of interneuron gene expression and function and a potential therapeutic target for neurological disorders associated with interneuron dysfunction.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Analysis of Variance
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Animals
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Animals, Newborn
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Biophysics
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Cells, Cultured
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DNA-Binding Proteins / metabolism
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Electric Stimulation / methods
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GTP Phosphohydrolases / metabolism
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Gene Expression Regulation, Developmental / genetics*
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Glutamate Decarboxylase / metabolism
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Heart
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High Mobility Group Proteins / metabolism
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Hippocampus / cytology
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Humans
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Inhibitory Postsynaptic Potentials / drug effects
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Inhibitory Postsynaptic Potentials / genetics
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Interneurons / metabolism
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Long-Term Potentiation / drug effects
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Long-Term Potentiation / genetics
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Myocardium / metabolism
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Parvalbumins / deficiency*
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Patch-Clamp Techniques / methods
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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RNA, Messenger / metabolism
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Shaw Potassium Channels / metabolism
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Trans-Activators / deficiency*
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Trans-Activators / metabolism
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Transcription Factors / metabolism
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Transfection / methods
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gamma-Aminobutyric Acid / metabolism*
Substances
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DNA-Binding Proteins
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GLUT4 enhancer factor, mouse
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High Mobility Group Proteins
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Parvalbumins
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Ppargc1a protein, mouse
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RNA, Messenger
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Shaw Potassium Channels
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Tfam protein, mouse
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Trans-Activators
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Transcription Factors
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gamma-Aminobutyric Acid
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GTP Phosphohydrolases
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Mfn2 protein, mouse
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Glutamate Decarboxylase
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glutamate decarboxylase 1
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glutamate decarboxylase 2