Network compensation of cyclic GMP-dependent protein kinase II knockout in the hippocampus by Ca2+-permeable AMPA receptors

Proc Natl Acad Sci U S A. 2015 Mar 10;112(10):3122-7. doi: 10.1073/pnas.1417498112. Epub 2015 Feb 23.


Gene knockout (KO) does not always result in phenotypic changes, possibly due to mechanisms of functional compensation. We have studied mice lacking cGMP-dependent kinase II (cGKII), which phosphorylates GluA1, a subunit of AMPA receptors (AMPARs), and promotes hippocampal long-term potentiation (LTP) through AMPAR trafficking. Acute cGKII inhibition significantly reduces LTP, whereas cGKII KO mice show no LTP impairment. Significantly, the closely related kinase, cGKI, does not compensate for cGKII KO. Here, we describe a previously unidentified pathway in the KO hippocampus that provides functional compensation for the LTP impairment observed when cGKII is acutely inhibited. We found that in cultured cGKII KO hippocampal neurons, cGKII-dependent phosphorylation of inositol 1,4,5-trisphosphate receptors was decreased, reducing cytoplasmic Ca(2+) signals. This led to a reduction of calcineurin activity, thereby stabilizing GluA1 phosphorylation and promoting synaptic expression of Ca(2+)-permeable AMPARs, which in turn induced a previously unidentified form of LTP as a compensatory response in the KO hippocampus. Calcineurin-dependent Ca(2+)-permeable AMPAR expression observed here is also used during activity-dependent homeostatic synaptic plasticity. Thus, a homeostatic mechanism used during activity reduction provides functional compensation for gene KO in the cGKII KO hippocampus.

Keywords: Ca2+-permeable AMPA receptors; LTP; calcineurin; gene knockout.

Publication types

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

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Cyclic GMP-Dependent Protein Kinase Type II / genetics
  • Cyclic GMP-Dependent Protein Kinase Type II / metabolism*
  • Hippocampus / drug effects
  • Hippocampus / enzymology*
  • Hippocampus / physiology
  • Homeostasis / drug effects
  • Long-Term Potentiation
  • Mice
  • Mice, Knockout
  • Phosphorylation
  • Receptors, AMPA / metabolism*
  • Synapses / enzymology
  • Synapses / metabolism
  • Tetrodotoxin / pharmacology


  • Receptors, AMPA
  • Tetrodotoxin
  • Cyclic GMP-Dependent Protein Kinase Type II
  • Calcium