Long-term potentiation can be induced in the CA1 region of hippocampus in the absence of αCaMKII T286-autophosphorylation

Abstract

a-calcium/calmodulin-dependent protein kinase (aCaMKII) T286-autophosphorylation provides a short-term molecular memory that was thought to be required for LTP and for learning and memory. However, it has been shown that learning can occur in aCaMKII-T286A mutant mice after a massed training protocol. This raises the question of whether there might be a form of LTP in these mice that can occur without T286 autophosphorylation. In this study, we confirmed that in CA1 pyramidal cells, LTP induced in acute hippocampal slices, after a recovery period in an interface chamber, is strictly dependent on postsynaptic aCaMKII autophosphorylation. However, we demonstrated that aCaMKII-autophosphorylation-independent plasticity can occur in the hippocampus but at the expense of synaptic specificity. This nonspecific LTP was observed in mutant and wild-type mice after a recovery period in a submersion chamber and was independent of NMDA receptors. Moreover, when slices prepared from mutant mice were preincubated during 2 h with rapamycin, high-frequency trains induced a synapse-specific LTP which was added to the nonspecific LTP. This specific LTP was related to an increase in the duration and the amplitude of NMDA receptor-mediated response induced by rapamycin.The formation of memories is believed to be achieved through strengthening of synaptic communication between two simultaneously active neurons, a phenomenon called long-term potentiation (LTP). For several years, numerous studies have sought to better understand the molecular mechanisms of synaptic plasticity and LTP, and in particular the role of calcium-calmodulin-dependent protein kinase II (CaMKII), one of the most important postsynaptic components in glutamatergic synapses. Indeed, CaMKII is both necessary and sufficient for LTP induction. The application of CaMKII inhibitors, such as KN-62 or KN-93, or genetic disruption of the CaMKII gene can block LTP (Malinow et al. 1989;Otmakhov et al. 1997;Hinds et al. 1998;Yamagata et al. 2009). Conversely, the injection or viral expression of a constitutively active form of CaMKII leads to the improvement of spatial memory (Poulsen et al. 2007), in enhancement of AMPAR-mediated synaptic transmission and occludes further induction of LTP (McGladeMcCulloh et al. 1993;Pettit et al. 1994;Lledo et al. 1995). This enhancement in AMPAR conductance has been proposed to occur through an increase in synaptic trafficking of GluA1 subunits, as well as phosphorylation of GluA1 at Ser831 (Shi et al. 1999;Hayashi et al. 2000;Broutman and Baudry 2001;Esteban et al. 2003;Oh et al. 2006). Besides its role in synaptic transmission, CaMKII is also involved in the structural plasticity of spines, and more specifically in activity-dependent spine growth following NMDAR activation (Okamoto et al. 2009;Pi et al. 2010). Moreover, it seems that CaMKII-dependent processes involved in hippocampal LTP in CA1 synapses are quite general since the kinase also affects in vivo plasticity in different brain regions (Wu and Cline 1998;Zou and Cline 1999). ...

CaMKII Autophosphorylation Is Necessary for Optimal Integration of Ca 2+ Signals during LTP Induction, but Not Maintenance

“…However, when we applied high frequency synaptic stimulation (40 Hz, 15 s; corresponding to ~8 Hz glutamate uncaging), LTP in Camk2a T286A mice was rescued (ΔEPSC = 76 ± 20%; Figure 4H, 4I). LTP induced by 40 Hz stimulation was abolished by the NMDAR antagonist APV, suggesting it is NMDAR-dependent (Figure S6A, S6B), unlike some other forms of LTP (Villers et al, 2014). To confirm that LTP induced by 40 Hz synaptic stimulation is CaMKII-dependent, we co-injected AAV encoding Cre and floxed-tdTM to the lateral ventricle of Camk2a fl/fl embryos.…”

Memory Erasure Experiments Indicate a Critical Role of CaMKII in Memory Storage

“…However, they only follow maintenance for short periods. Other work using the same mutation (Villers et al, 2014) measured LTP over longer periods and found that normal LTP was not maintained but, rather, was replaced by a form of potentiation that does not have synapse specificity or NMDAR dependence. In summary, the model of (Chang et al, 2017; Murakoshi et al, 2017) leaves a large number of experimental results demonstrating long-lasting changes in CaMKII unexplained (Ahmed and Frey, 2005; Fukunaga et al, 1993; Lengyel et al, 2004; Otmakhov et al, 2004) and is inconsistent with results showing that manipulations of CaMKII during the maintenance period can affect LTP (Barcomb et al, 2016; Sanhueza et al, 2011) and behavior (Figs.…”

CaMKII mediates stimulus specificity in early odor preference learning in rats

“…Activation of CaMKII leads to enhance-ment of synaptic transmission, and LTP is occluded by increasing the concentrations of constitutively active CaMKII (Pettit et al 1994). The role of CaMKII as a synaptic tag that mediates synapse-specific LTP has been shown in hippocampal CA1 of ␣CaMKII-T286A mutant mice (Villers et al 2014). Several forms of LTP can be induced in these mice but at the expense of synaptic input specificity.…”

“…Several forms of LTP can be induced in these mice but at the expense of synaptic input specificity. In the absence of ␣CaMKII autophosphorylation, LTP is not restricted to stimulated synapses (Villers et al 2014). However, the role of CaMKII in the stimulus specificity of natural learning and memory has not been addressed explicitly.…”