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- Title
Decreased nitrosylation of CaMKII causes aging-associated impairments in memory and synaptic plasticity in mice.
- Authors
Rumian, Nicole L.; Freund, Ronald K.; Dell'Acqua, Mark L.; Coultrap, Steven J.; Bayer, K. Ulrich
- Abstract
CaMKII has molecular memory functions because transient calcium ion stimuli can induce long-lasting increases in its synaptic localization and calcium ion–independent (autonomous) activity, thereby leaving memory traces of calcium ion stimuli beyond their duration. The synaptic effects of two mechanisms that induce CaMKII autonomy are well studied: autophosphorylation at threonine-286 and binding to GluN2B. Here, we examined the neuronal functions of additional autonomy mechanisms: nitrosylation and oxidation of the CaMKII regulatory domain. We generated a knock-in mouse line with mutations that render the CaMKII regulatory domain nitrosylation/oxidation-incompetent, CaMKIIΔSNO, and found that it had deficits in memory and synaptic plasticity that were similar to those in aged wild-type mice. In addition, similar to aged wild-type mice, in which CaMKII was hyponitrosylated, but unlike mice with impairments of other CaMKII autonomy mechanisms, CaMKIIΔSNO mice showed reduced long-term potentiation (LTP) when induced by theta-burst stimulation but not high-frequency stimulation (HFS). As in aged wild-type mice, the HFS-LTP in the young adult CaMKIIΔSNO mice required L-type voltage-gated calcium ion channels. The effects in aged mice were likely caused by the loss of nitrosylation because no decline in CaMKII oxidation was detected. In hippocampal neurons, nitrosylation of CaMKII induced its accumulation at synapses under basal conditions in a manner mediated by GluN2B binding, like after LTP stimuli. However, LTP-induced synaptic CaMKII accumulation did not require nitrosylation. Thus, an aging-associated decrease in CaMKII nitrosylation may cause impairments by chronic synaptic effects, such as the decrease in basal synaptic CaMKII. Editor's summary: Cognitive function declines with age, as does the amount of S-nitrosylated proteins in the brain. One such protein is the kinase CaMKII, which in neurons mediates synaptic signaling that supports learning and memory. Rumian et al. found that S-nitrosylation of CaMKII was critical for the localization of the kinase to synapses and for the response of hippocampal neurons to a stimulus that mimics experience-induced brain activity. Cognitive function in young mice expressing S-nitrosylation–deficient CaMKII was impaired to similar extents as those seen in older, wild-type mice. The findings reveal a mechanism of age-related cognitive decline. —Leslie K. Ferrarelli
- Subjects
NEUROPLASTICITY; NITROSYLATION; MEMORY disorders; VOLTAGE-gated ion channels; ION channels; CALCIUM ions
- Publication
Science Signaling, 2023, Vol 16, Issue 795, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.ade5892