CaM kinase II and protein kinase C activations mediate enhancement of long-term potentiation by nefiracetam in the rat hippocampal CA1 region
Version of Record online: 28 APR 2008
© 2008 The Authors. Journal Compilation © 2008 International Society for Neurochemistry
Journal of Neurochemistry
Volume 106, Issue 3, pages 1092–1103, August 2008
How to Cite
Moriguchi, S., Shioda, N., Han, F., Narahashi, T. and Fukunaga, K. (2008), CaM kinase II and protein kinase C activations mediate enhancement of long-term potentiation by nefiracetam in the rat hippocampal CA1 region. Journal of Neurochemistry, 106: 1092–1103. doi: 10.1111/j.1471-4159.2008.05440.x
- Issue online: 15 JUL 2008
- Version of Record online: 28 APR 2008
- Received February 19, 2008; revised manuscript received April 3, 2008; accepted April 22, 2008.
- Alzheimer’s disease;
- calcium/calmodulin-dependent protein kinase II;
- long-term potentiation;
- N-methyl-d-aspartate acid;
- protein kinase C
Nefiracetam is a pyrrolidine-related nootropic drug exhibiting various pharmacological actions such as cognitive-enhancing effect. We previously showed that nefiracetam potentiates NMDA-induced currents in cultured rat cortical neurons. To address questions whether nefiracetam affects NMDA receptor-dependent synaptic plasticity in the hippocampus, we assessed effects of nefiracetam on NMDA receptor-dependent long-term potentiation (LTP) by electrophysiology and LTP-induced phosphorylation of synaptic proteins by immunoblotting analysis. Nefiracetam treatment at 1–1000 nM increased the slope of fEPSPs in a dose-dependent manner. The enhancement was associated with increased phosphorylation of α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor through activation of calcium/calmodulin-dependent protein kinase II (CaMKII) without affecting synapsin I phosphorylation. In addition, nefiracetam treatment increased PKCα activity in a bell-shaped dose–response curve which peaked at 10 nM, thereby increasing phosphorylation of myristoylated alanine-rich protein kinase C substrate and NMDA receptor. Nefiracetam treatment did not affect protein kinase A activity. Consistent with the bell-shaped PKCα activation, nefiracetam treatment enhanced LTP in the rat hippocampal CA1 region with the same bell-shaped dose–response curve. Furthermore, nefiracetam-induced LTP enhancement was closely associated with CaMKII and PKCα activation with concomitant increases in phosphorylation of their endogenous substrates except for synapsin I. These results suggest that nefiracetam potentiates AMPA receptor-mediated fEPSPs through CaMKII activation and enhances NMDA receptor-dependent LTP through potentiation of the post-synaptic CaMKII and protein kinase C activities. Together with potentiation of nicotinic acetylcholine receptor function, nefiracetam-enhanced AMPA and NMDA receptor functions likely contribute to improvement of cognitive function.