Spatial memory deficits and motor coordination facilitation in cGMP-dependent protein kinase type II-deficient mice

Abstract

Activity-dependent trafficking of AMPA receptors to synapses regulates synaptic strength. Activation of the NMDA receptor induces several second messenger pathways that contribute to receptor trafficking-dependent plasticity, including the NO pathway, which elevates cGMP. In turn, cGMP activates the cGMP-dependent protein kinase type II (cGKII), which phosphorylates the AMPA receptor subunit GluA1 at serine 845, a critical step facilitating synaptic delivery in the mechanism of activity-dependent synaptic potentiation. Since cGKII is expressed in the striatum, amygdala, cerebral cortex, and hippocampus, it has been proposed that mice lacking cGKII may present phenotypic differences compared to their wild-type littermates in emotion-dependent tasks, learning and memory, and drug reward salience. Previous studies have shown that cGKII KO mice ingest higher amounts of ethanol as well as exhibit elevated anxiety levels compared to wild-type (WT) littermates. Here, we show that cGKII KO mice are significantly deficient in spatial learning while exhibiting facilitated motor coordination, demonstrating a clear dependence of memory-based tasks on cGKII. We also show diminished GluA1 phosphorylation in the postsynaptic density (PSD) of cGKII KO prefrontal cortex while in hippocampal PSD fractions, phosphorylation was not significantly altered. These data suggest that the role of cGKII may be more robust in particular brain regions, thereby impacting complex behaviors dependent on these regions differently.

Network compensation of cyclic GMP-dependent protein kinase II knockout in the hippocampus by Ca 2+ -permeable AMPA receptors

“…This suggests that cGK-mediated NO signaling plays critical roles in the striatum. We also have shown previously that levels of pGluA1(S845) are reduced in the PSD of the prefrontal cortex (PFC) in the KO relative to WT (42). Thus, unlike the hippocampus, there are kinase-deficiency phenotypes in the PFC and striatum, indicating that the compensatory mechanism we have demonstrated here may not act globally in the KO.…”

“…Taken together, although hippocampal LTP in the cGKII KO appears to be normal, a distinct pathway is used. Indeed, our recent findings that cGKII KO mice display behavioral abnormalities (41,42) suggest that the compensatory mechanism is imperfect and does not fully restore cGKIIdependent function.…”

Brain region-specific effects of cGMP-dependent kinase II knockout on AMPA receptor trafficking and animal behavior

“…Taken together these studies in various brain regions, amygdala, hippocampus, nucleus accumbens and olfactory bulb, plus our previous study of prefrontal cortex (Wincott et al 2013;Kim et al 2015a), show a strong correlation between the regional expression of GluA1-pS845 and behaviors requiring those brain areas, suggesting a predictive role for GluA1-pS845 in a behavioral readout.…”

“…Furthermore, tissue or region-specificity of inhibition of target functions in the brain is particularly important for drug design (Petrovskiy et al 2015). Our previous studies of the hippocampus and PFC in cGKII KO mice have suggested that effects of cGKII KO on GluA1 phosphorylation are region-specific (Wincott et al 2013;Kim et al 2015a). Studies of various mental illnesses have demonstrated an important role for AMPARs in maintaining behavior (Kessels and Malinow 2009;Chang et al 2012).…”

“…In the KO hippocampus, synaptic GluA1-pS845 is increased, expressing GluA2-lacking Ca 2+ -permeable AMPARs, which provides a novel form of LTP as a compensatory response to the genetic deletion of cGKII (Kim et al 2015a). However, we have shown that this compensation is restricted to the hippocampus since GluA1-pS845 is significantly reduced in the prefrontal cortex (PFC) (Wincott et al 2013). …”