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Potentiation of glutamatergic synaptic transmission is thought to underlie memory. The induction of this synaptic potentiation relies on activation of NMDA receptors which allows for calcium influx into the post-synapse. A key mechanistic question for the understanding of synaptic potentiation is what signaling is activated by the calcium influx. Here, I review evidences that at mature synapses the elevated calcium levels activate primarily calcium/calmodulin-dependent kinase II (CaMKII) and cause its autophophorylation. CaMKII autophosphorylation leads to calcium-independent activity of the kinase, so that kinase signaling can outlast NMDA receptor-dependent calcium influx. Prolonged CaMKII signaling induces downstream signaling for AMPA receptor trafficking into the post-synaptic density and causes structural enlargement of the synapse. Interestingly, however, CaMKII autophosphorylation does not have such an essential role in NMDA receptor-dependent synaptic potentiation in early postnatal development and in adult dentate gyrus, where neurogenesis occurs. Additionally, in old age memory-relevant NMDA receptor-dependent synaptic plasticity appears to be due to generation of multi-innervated dendritic spines, which does not require CaMKII autophosphorylation. In conclusion, CaMKII autophosphorylation has a conditional role in the induction of NMDA receptor-dependent synaptic potentiation., (Copyright © 2021. Published by Elsevier Ltd.)

Autophosphorylation of αCaMKII is regarded as a 'molecular memory' for Ca(2+) transients and a crucial mechanism in aversely, but less so in appetitively, motivated learning and memory. While there is a growing body of research implicating αCaMKII in general in behavioral responses to threat or fearful stimuli, little is known about the contribution of the autophosphorylation. The present study asked how αCaMKII autophosphorylation controls anxiety-like behavioral responses toward novel, potentially threatening stimuli. We tested homozygous and heterozygous T286A αCaMKII autophosphorylation deficient mice and wild types in a systematic series of behavioral tests. Homozygous mutants were more active in the open field test and showed reduced anxiety-related behavior in the light/dark test, but these findings were confounded by a hyperlocomotor phenotype. The analysis of elevated plus maze showed significantly reduced anxiety-related behavior in the αCaMKII autophosphorylation-deficient mice which appeared to mediate a hyperlocomotor response. An analysis of home cage behavior, where neither novel nor threatening stimuli were present, showed no differences in locomotor activity between genotypes. Increased locomotion was not observed in the novel object exploration test in the αCaMKII autophosphorylation-deficient mice, implying that hyperactivity does not occur in response to discrete novel stimuli. The present data suggest that the behavior of αCaMKII autophosphorylation-deficient mice cannot simply be described as a low anxiety phenotype. Instead it is suggested that αCaMKII autophosphorylation influences locomotor reactivity to novel environments that are potentially, but not necessarily threatening., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Previous results have suggested that the Ras signaling pathway is involved in learning and memory. Ras is activated by nucleotide exchange factors, such as the calmodulin-activated guanine-nucleotide releasing factor 1 (Ras-GRF1). To test whether Ras-GRF1 is required for learning and memory, we inactivated the Ras-GRF1 gene in mice. These mutants performed normally in a rota-rod motor coordination task, and in two amygdala-dependent tasks (inhibitory avoidance and contextual conditioning). In contrast the mutants were impaired in three hippocampus-dependent learning tasks: contextual discrimination, the social transmission of food preferences, and the hidden-platform version of the Morris water maze. These studies indicate that Ras-GRF1 plays a role in hippocampal-dependent learning and memory.