Sex differences in GABA(B)R-GIRK signaling in layer 5/6 pyramidal neurons of the mouse prelimbic cortex

Neuropharmacology. 2015 Aug;95:353-60. doi: 10.1016/j.neuropharm.2015.03.029. Epub 2015 Apr 2.


The medial prefrontal cortex (mPFC) has been implicated in multiple disorders characterized by clear sex differences, including schizophrenia, attention deficit hyperactivity disorder, post-traumatic stress disorder, depression, and drug addiction. These sex differences likely represent underlying differences in connectivity and/or the balance of neuronal excitability within the mPFC. Recently, we demonstrated that signaling via the metabotropic γ-aminobutyric acid receptor (GABABR) and G protein-gated inwardly-rectifying K(+) (GIRK/Kir3) channels modulates the excitability of the key output neurons of the mPFC, the layer 5/6 pyramidal neurons. Here, we report a sex difference in the GABABR-GIRK signaling pathway in these neurons. Specifically, GABABR-dependent GIRK currents recorded in the prelimbic region of the mPFC were larger in adolescent male mice than in female counterparts. Interestingly, this sex difference was not observed in layer 5/6 pyramidal neurons of the adjacent infralimbic cortex, nor was it seen in young adult mice. The sex difference in GABABR-GIRK signaling is not attributable to different expression levels of signaling pathway components, but rather to a phosphorylation-dependent trafficking mechanism. Thus, sex differences related to some diseases associated with altered mPFC function may be explained in part by sex differences in GIRK-dependent signaling in mPFC pyramidal neurons.

Keywords: GABA; GIRK; Kir3; Medial prefrontal cortex; Sex differences; Slice electrophysiology.

Publication types

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

MeSH terms

  • Animals
  • Female
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / genetics
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / metabolism*
  • Immunoblotting
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Immunoelectron
  • Patch-Clamp Techniques
  • Phosphorylation / physiology
  • Prefrontal Cortex / growth & development
  • Prefrontal Cortex / physiology*
  • Prefrontal Cortex / ultrastructure
  • Pyramidal Cells / physiology*
  • Real-Time Polymerase Chain Reaction
  • Receptors, GABA-B / metabolism*
  • Sex Characteristics*
  • Signal Transduction / physiology
  • Tissue Culture Techniques


  • G Protein-Coupled Inwardly-Rectifying Potassium Channels
  • Receptors, GABA-B