Mice lacking the transcriptional coactivator PGC-1α exhibit alterations in inhibitory synaptic transmission in the motor cortex.
Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a transcriptional coactivator known to regulate gene programs in a cell-specific manner in energy-demanding tissues, and its dysfunction has been implicated in numerous neurological and psychiatric disorders. Previous work from the Cowell laboratory indicates that PGC-1α is concentrated in inhibitory interneurons and is required for the expression of the calcium buffer parvalbumin (PV) in the cortex; however, the impact of PGC-1α deficiency on inhibitory neurotransmission in the motor cortex is not known. Here, we show that mice lacking PGC-1α exhibit increased amplitudes and decreased frequency of spontaneous inhibitory postsynaptic currents in layer V pyramidal neurons. Upon repetitive train stimulation at the gamma frequency, decreased GABA release is observed. Furthermore, PV-positive interneurons in PGC-1α -/- mice display reductions in intrinsic excitability and excitatory input without changes in gross interneuron morphology. Taken together, these data show that PGC-1α is required for normal inhibitory neurotransmission and cortical PV-positive interneuron function. Given the pronounced motor dysfunction in PGC-1α -/- mice and the essential role of PV-positive interneurons in maintenance of cortical excitatory:inhibitory balance, it is possible that deficiencies in PGC-1α expression could contribute to cortical hyperexcitability and motor abnormalities in multiple neurological disorders.
University of Alabama Birmingham, Department of Psychiatry & Behavioral Neurobiology, United States.
S E
SE
Dougherty
University of Alabama Birmingham, Department of Neurobiology, Evelyn F. McKnight Brain Institute, Civitan International Research Center, United States.
A F
AF
Bartley
University of Alabama Birmingham, Department of Psychiatry & Behavioral Neurobiology, United States.
E K
EK
Lucas
University of Alabama Birmingham, Department of Neurobiology, Evelyn F. McKnight Brain Institute, Civitan International Research Center, United States.
J J
JJ
Hablitz
University of Alabama Birmingham, Department of Neurobiology, Evelyn F. McKnight Brain Institute, Civitan International Research Center, United States. Electronic address: dobrunz@uab.edu.
L E
LE
Dobrunz
University of Alabama Birmingham, Department of Psychiatry & Behavioral Neurobiology, United States. Electronic address: rcowell@uab.edu.
R M
RM
Cowell
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D004558:Electric Stimulation; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D053444:Inhibitory Postsynaptic Potentials / Q000502:physiology; D007395:Interneurons / Q000473:pathology / Q000502:physiology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009044:Motor Cortex / Q000473:pathology / Q000502:physiology*; D009433:Neural Inhibition / Q000502:physiology*; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D010320:Parvalbumins / Q000378:metabolism; D018408:Patch-Clamp Techniques; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017966:Pyramidal Cells / Q000473:pathology / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology*; D046509:Tissue Culture Techniques; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D010320:Parvalbumins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D005680:gamma-Aminobutyric Acid
inhibitory neurotransmission; interneuron; motor cortex; parvalbumin; peroxisome proliferator-activated receptor gamma coactivator 1α