Potentiated Transmission and Prevention of Further LTP by Increased CaMKII activity in Postsynaptic Hippocampal Slice Neurons

Abstract

Calcium-calmodulin-dependent protein kinase II (CaMKII) is a necessary component of the cellular machinery underlying learning and memory. Here, a constitutively active form of this enzyme, CaMKII(1-290), was introduced into neurons of hippocampal slices with a recombinant vaccinia virus to test the hypothesis that increased postsynaptic activity of this enzyme is sufficient to produce long-term synaptic potentiation (LTP), a prominent cellular model of learning and memory. Postsynaptic expression of CaMKII(1-290) increased CaMKII activity, enhanced synaptic transmission, and prevented more potentiation by an LTP-inducing protocol. These results, together with previous studies, suggest that postsynaptic CaMKII activity is necessary and sufficient to generate LTP.

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).…”

Translocation of Autophosphorylated Calcium/Calmodulin-dependent Protein Kinase II to the Postsynaptic Density

“…CaMKII␣ knockout mice show impaired hippocampal long term potentiation, a cellular model for learning and memory (12). Conversely, introduction of CaMKII␣ into neurons augments postsynaptic responses and occludes further electrically induced long term potentiation (13,14).CaMKII␣ undergoes calcium/calmodulin-dependent autophosphorylation on Thr 286 in its regulatory domain, rendering the kinase partially calcium-independent (1, 2). This reaction has been proposed as a "molecular switch," translating transient calcium elevation into prolonged kinase activity (15, 16), which becomes subject to regulation by protein phosphatases.…”

“…CaMKII␣ knockout mice show impaired hippocampal long term potentiation, a cellular model for learning and memory (12). Conversely, introduction of CaMKII␣ into neurons augments postsynaptic responses and occludes further electrically induced long term potentiation (13,14).…”

Regulation of AMPA receptors and synaptic plasticity

“…Postsynaptic expression of a constitutively active form of CaMKII in hippocampal slices enhances synaptic transmission and prevents further induction of LTP, suggesting that CaMKII and LTP upregulate synaptic transmission through the same mechanism (Pettit et al, 1994;Lledo et al, 1998). The effect of constitutively active CaMKII on synaptic delivery of GluR1 is abrogated by inhibition of PKA, but activation of PKA signaling independently is not enough to induce delivery of the receptors to the synapse (Esteban et al, 2003a).…”