Parvalbumin deficiency and GABAergic dysfunction in mice lacking PGC-1alpha.
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.
Lucas
Elizabeth K
EK
Department of Psychology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Markwardt
Sean J
SJ
Gupta
Swati
S
Meador-Woodruff
James H
JH
Lin
Jiandie D
JD
Overstreet-Wadiche
Linda
L
Cowell
Rita M
RM
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001703:Biophysics; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004558:Electric Stimulation / Q000379:methods; D020558:GTP Phosphohydrolases / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006321:Heart; D006609:High Mobility Group Proteins / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D007395:Interneurons / Q000378:metabolism; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D010320:Parvalbumins / Q000172:deficiency*; D018408:Patch-Clamp Techniques / Q000379:methods; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger / Q000378:metabolism; D051670:Shaw Potassium Channels / Q000378:metabolism; D015534:Trans-Activators / Q000172:deficiency* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection / Q000379:methods; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D004268:DNA-Binding Proteins; C528734:GLUT4 enhancer factor, mouse; D006609:High Mobility Group Proteins; D010320:Parvalbumins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D012333:RNA, Messenger; D051670:Shaw Potassium Channels; C081930:Tfam protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D005680:gamma-Aminobutyric Acid; D020558:GTP Phosphohydrolases; C488751:Mfn2 protein, mouse; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; C401141:glutamate decarboxylase 2