Sex differences in GABABR-GIRK signaling in layer 5/6 pyramidal neurons of the mouse prelimbic cortex

Ezequiel Marron Fernandez De Velasco, Matthew Hearing, Zhilian Xia, Nicole C. Victoria, Rafael Luján, Kevin Wickman

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)353-360
Number of pages8
StatePublished - Aug 1 2015

Bibliographical note

Funding Information:
The authors would like to thank Daniele Young, Jennifer Kutzke, and Alex Shnaydruk for maintaining the mouse colony. This work was supported by NIH grants to MH ( DA007097 ), NCV ( DA007234 ), and KW ( MH061933 and DA034696 ), and by grants from the Spanish Ministry of Education and Science to RL ( BFU-2012-38348 ).

Publisher Copyright:
© 2015 Elsevier Ltd. All rights reserved.


  • GABA
  • GIRK
  • Kir3
  • Medial prefrontal cortex
  • Sex differences
  • Slice electrophysiology


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