An essential role for postsynaptic calmodulin and protein kinase activity in long-term potentiation

Abstract

The phenomenon of long-term potentiation (LTP), a long lasting increase in the strength of synaptic transmission which is due to brief, repetitive activation of excitatory afferent fibres, is one of the most striking examples of synaptic plasticity in the mammalian brain. In the CA1 region of the hippocampus, the induction of LTP requires activation of NMDA (N-methyl-D-aspartate) receptors by synaptically released glutamate with concomitant postsynaptic membrane depolarization. This relieves the voltage-dependent magnesium block of the NMDA-receptor ion channel, allowing calcium to flow into the dendritic spine. Although calcium has been shown to be a necessary trigger for LTP (refs 11, 12), little is known about the immediate biochemical processes that are activated by calcium and are responsible for LTP. The most attractive candidates have been calcium/calmodulin-dependent protein kinase II (CaM-KII) (refs 13-16), protein kinase C (refs 17-19), and the calcium-dependent protease, calpain. Extracellular application of protein kinase inhibitors to the hippocampal slice preparation blocks the induction of LTP (refs 21-23) but it is unclear whether this is due to a pre- and/or postsynaptic action. We have found that intracellular injection into CA1 pyramidal cells of the protein kinase inhibitor H-7, or of the calmodulin antagonist calmidazolium, blocks LTP. Furthermore, LTP is blocked by the injection of synthetic peptides that are potent calmodulin antagonists and inhibit CaM-KII auto- and substrate phosphorylation. These findings demonstrate that in the postsynaptic cell both activation of calmodulin and kinase activity are required for the generation of LTP, and focus further attention on the potential role of CaM-KII in LTP.

Advances in behavioral genetics: mouse models of autism

“…The authors attributed this change to a shift toward reduced cortical excitability and an enhanced inhibitory drive in the model of Rett syndrome, rather than to any intrinsic anomaly in the neurons themselves. 125 Ca þ 2 /calmodulin-dependent protein kinase II (CaMKII) is an important mediator of LTP [126][127][128][129][130] and other forms of synaptic plasticity. 131 Stimuli that induce LTP also persistently activate CaMKII, which may be critical for the molecular memory of synaptic events.…”

αCaMKII autophosphorylation levels differ depending on subcellular localization

“…In particular, this kinase is widely believed to be a critical mediator of long term potentiation (LTP), a cellular mechanism that is thought to underlie learning and memory (Bliss and Collingridge, 1993). Several studies have demonstrated that CaMKII is necessary for the induction of LTP (Malinow et al, 1989;Malenka et al, 1989;Silva et al, 1992;Giese et al, 1998), and that introduction of activated CaMKII is sufficient to potentiate synaptic responses in neurons (Pettit et al, 1994;Lledo et al, 1995;McGlade-McCulloh et al, 1993). CaMKII is enriched at the postsynaptic density (PSD) (Kennedy et al, 1983;Suzuki et al, 1994;Petersen et al, 2003), a protein-dense specialization at the post-synaptic membrane that is composed primarily of scaffolding proteins, ion channels, and signal transduction enzymes (Ziff, 1997).…”

Cyclic nucleotide–gated channels, calmodulin, adenylyl cyclase, and calcium/calmodulin-dependent protein kinase II are required for late, but not early, long-term memory formation in the honeybee

“…Although a large number of studies have investigated the effects of impairing enzymes targeted by CaM (e.g., NOS, CaMKII, MAPK) on learning and memory, there are relatively few reports about the effects of direct inhibition of CaM (Malenka et al 1989;Nakazawa et al 1995;Margrie et al 1998;Limback-Stokin et al 2004). We investigated the effect of CaM inhibition on olfactory learning and memory in honeybees using three structurally different CaM antagonists, W-7, TFP, and R24571, delivered at different concentrations (Fig.…”