Autophosphorylation of αCaMKII is not a general requirement for NMDA receptor‐dependent LTP in the adult mouse

Abstract

Autophosphorylation of α‐Ca2+/calmodulin kinase II (αCaMKII) at Thr286 is thought to be a general effector mechanism for sustaining transcription‐independent long‐term potentiation (LTP) at pathways where LTP is NMDA receptor‐dependent. We have compared LTP at two such hippocampal pathways in mutant mice with a disabling point mutation at the Thr286 autophosphorylation site. We find that autophosphorylation of αCaMKII is essential for induction of LTP at Schaffer commissural–CA1 synapses in vivo, but is not required for LTP that can be sustained over days at medial perforant path–granule cell synapses in awake mice. At these latter synapses LTP is supported by cyclic AMP‐dependent signalling in the absence of αCaMKII signalling. Thus, the autophosphorylation of αCaMKII is not a general requirement for NMDA receptor‐dependent LTP in the adult mouse.

Mechanism for long-term memory formation when synaptic strengthening is impaired

“…The T286A mutants can form contextual LTM although they have fully blocked NMDA receptor-dependent synaptic strengthening in hippocampal area CA1, as indicated by previous electrophysiological experiments (10)(11)(12)(13)(14). We confirmed that late CA1 LTP is blocked after strong electrical stimulation, and we show that training-induced synaptic strengthening is deficient in hippocampal area CA1, in the amygdala, neocortex, and striatum, and in the T286A mutants, using imaging of the expression of three IEGs (Zif268, c-Fos, and Nur77) that are critical transcription factors for long-lasting synaptic strengthening (17,18).…”

“…T286A mutants have substantial deficits in synaptic strengthening induced by electrical stimulation (10)(11)(12)(13)(14). The expression of the IEGs Zif268 and c-Fos has been shown to be a prerequisite for late LTP (17,18).…”

“…Those studies, however, did not establish whether synaptogenesis contributes to memory as functional plasticity and modulation of neuronal excitability could be sufficient. Using αCaMKII autophosphorylation-deficient (T286A) mutants, which have impaired NMDA receptor-dependent synaptic strengthening (10)(11)(12)(13)(14) and deficits in the regulation of the AHP in CA1 pyramidal neurons (15), we demonstrate that contextual LTM formation is linked with PSD95 up-regulation and persistent MIS generation. Both, the PSD95 up-regulation and contextual LTM formation in T286A mutants require the mTOR kinase in the hippocampus.…”

“…As a proxy, here we have studied T286A missense mutant mice lacking autophosphorylation at threonine 286 of the α-isoform of calcium/calmodulindependent kinase II (αCaMKII), a major protein of glutamatergic synapses in the forebrain (11). The T286A mutants have fully blocked NMDA receptor-dependent synaptic strengthening at hippocampal CA1 synapses (11)(12)(13)(14), and they have impaired regulation of the postburst afterhyperpolarization (AHP) in CA1 pyramidal neurons (15). Accordingly, T286A mutants are deficient in contextual fear conditioning after a single training trial (16).…”

Autophosphorylation of αCaMKII is differentially involved in new learning and unlearning mechanisms of memory extinction

“…A broad range of genetic lesions of ␣CaMKII signaling has been demonstrated to block both learning and LTP (Elgersma et al 2004). In particular, autophosphorylation of ␣CaMKII at threonine-286 in response to Ca 2+ influx, which switches the kinase into a Ca 2+ /calmodulin-independent or autonomously active state, provides a crucial step (Miller and Kennedy 1986;Fukunaga et al 1995;Tan and Liang 1996;Ouyang et al 1997;Rodrigues et al 2004), since knock-in mice with a targeted point mutation (T286A) that prevents autophosphorylation at this site exhibit deficits in hippocampal LTP and memory formation (Giese et al 1998;Ohno et al 2002Ohno et al , 2005Ohno et al , 2006Need and Giese 2003;Irvine et al 2005;Cooke et al 2006). Although the mechanisms by which ␣CaMKII autophosphorylation contributes to learning have been well documented, its role in memory extinction remains to be determined.…”