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

Significance Deletion of genes in organisms does not always give rise to phenotypes because of the existence of compensation, even though phenotypes may be found when gene activity is blocked acutely. The cGMP-dependent kinase II knockout is a typical example of this apparent paradox. The knockout shows no evident impairment of LTP, whereas acute inhibition of kinase activity significantly decreases it. This paper describes a previously unidentified form of network-based compensation for cGMP-dependent kinase II gene knockout that is not dependent on expression of duplicate or paralogous genes. Furthermore, the compensation described here is mediated by a mechanism similar to that used by activity-dependent homeostatic synaptic plasticity, suggesting that neurons in complex brains may overcome an unexpected genetic lesion by using existing homeostatic mechanisms. 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.