Hippocampal Synaptic Metaplasticity Requires Inhibitory Autophosphorylation of Ca²⁺/Calmodulin-Dependent Kinase II

Abstract

Virtually all CNS synapses display the potential for activity-dependent long-term potentiation (LTP) and/or long-term depression (LTD).Intriguingly, the potential to exhibit LTP or LTD at many central synapses itself is powerfully modulated by previous synaptic activity. This higher-order form of plasticity has been termed metaplasticity. Here, we show that inhibitory autophosphorylation of Ca 2ϩ / calmodulin-dependent kinase II (CaMKII) is required for hippocampal metaplasticity at the lateral perforant path-dentate granule cell synapse. Brief 10 Hz priming, which does not affect basal synaptic transmission, caused a dramatic, pathway-specific and long-lasting (up to 18 h) reduction in subsequently evoked LTP at lateral perforant path synapses. In contrast, LTD was unaffected by priming. The induction of lateral perforant path metaplasticity required the activation of NMDA receptors during priming. In addition, metaplasticity was absent in knock-in mice expressing ␣CaMKII that cannot undergo inhibitory phosphorylation, indicating that inhibitory autophosphorylation of ␣CaMKII at threonines 305/306 is required for metaplasticity. Metaplasticity was not observed in the medial perforant pathway, consistent with the observation that CaMKII activity was not required for the induction of LTP at this synapse. Thus, modulation of ␣CaMKII activity via autophosphorylation at Thr305/Thr306 is a key mechanism for metaplasticity that may be of importance in the integration of temporally separated episodes of activity.

Hippocampal Metaplasticity Induced by Deficiency in the Extracellular Matrix Glycoprotein Tenascin-R

“…Previous analysis of mouse mutants has revealed that abnormalities in expression of glutamate receptors and intracellular signal transducing molecules, such as the nonreceptor tyrosine kinase fyn, Ca 2ϩ /calmodulin-dependent protein kinase II, postsynaptic density-95, and neurogranin lead to metaplastic changes in the hippocampus (Mayford et al, 1995;Kiyama et al, 1998;Lu et al, 1999;Migaud et al, 1998;Krucker et al, 2002;Huang et al, 2004;Zhang et al, 2005). Here, we have discovered an extracellular matrix molecule involved in metaplasticity.…”

Stable Learning in Stochastic Network States

“…A likely candidate to mediate metaplasticity processes was suggested to be an autophosphorylated state of calcium/calmodulin kinase II (CaMKII) (Bear, 1995;Mayford et al, 1995;Giese et al, 1998). In particular, autophosphorylation at site Thr305/306 has a suppressive effect on the calmodulin kinase binding, acting on a very slow timescale as described in our model (Elgersma et al, 2002;Zhang et al, 2005). The phosphorylation state at these sites has been shown recently to play a pivotal role in the induction of LTP and LTD, thus being an ideal candidate for the regulation of the BCM sliding threshold (Pi et al, 2010).…”

Calcium threshold shift enables frequency-independent control of plasticity by an instructive signal

“…43). Moreover, it has been demonstrated that priming-induced Thr305/306 phosphorylation prevents subsequent LTP induction (32). In these examples, threshold shifts follow prior synaptic activity; thus, they constitute forms of metaplasticity as predicted by the BCM rule.…”

“…Negative regulation of CaMKII by Thr305/ 306 autophosphorylation requires prior calcium/calmodulin-mediated activation of CaMKII and subsequent calmodulin dissociation (31). Moreover, it has been shown that Thr305/306 phosphorylation, triggered by 10-Hz priming, reduces hippocampal LTP (32), whereas genetic manipulation of the Thr305/306 phosphorylation site lowers the LTP threshold and prevents priming (27,32). Thus, CaMKII inhibitory autophosphorylation depends on previous calcium signaling and directly affects the kinase/phosphatase balance, thus fulfilling the two requirements outlined above.…”