Mice Lacking the Transcriptional Coactivator PGC-1α Exhibit Alterations in Inhibitory Synaptic Transmission in the Motor Cortex

Neuroscience. 2014 Jun 20;271:137-48. doi: 10.1016/j.neuroscience.2014.04.023. Epub 2014 Apr 24.

Abstract

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.

Keywords: inhibitory neurotransmission; interneuron; motor cortex; parvalbumin; peroxisome proliferator-activated receptor gamma coactivator 1α.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / physiology
  • Animals
  • Electric Stimulation
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Inhibitory Postsynaptic Potentials / physiology
  • Interneurons / pathology
  • Interneurons / physiology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Motor Cortex / pathology
  • Motor Cortex / physiology*
  • Neural Inhibition / physiology*
  • Neurons / pathology
  • Neurons / physiology*
  • Parvalbumins / metabolism
  • Patch-Clamp Techniques
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Pyramidal Cells / pathology
  • Pyramidal Cells / physiology
  • Synaptic Transmission / physiology*
  • Tissue Culture Techniques
  • Transcription Factors / deficiency*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • gamma-Aminobutyric Acid / metabolism

Substances

  • Parvalbumins
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Transcription Factors
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • gamma-Aminobutyric Acid