Phosphatidylinositol 3 Kinase Activation and AMPA Receptor Subunit Trafficking Underlie the Potentiation of Miniature EPSC Amplitudes Triggered by the Activation of L-Type Calcium Channels

Abstract

We have characterized a mechanism by which the amplitudes of miniature EPSCs (mEPSCs) in CA1 pyramidal neurons in rat hippocampal organotypic slice cultures are potentiated by approximately twofold after a series of depolarizing voltage pulses from -80 to ϩ20 mV. The increase in mEPSC amplitudes is triggered by the activation of L-type calcium channels and is independent of NMDA receptor (NMDAR) activation but also requires calcium release from intracellular stores. The potentiation induced by depolarizing pulses does not alter the kinetic parameters of mEPSCs. The induction phase of this potentiation involves phosphatidylinositol 3 kinase (PI3 kinase) activation because it is blocked completely in the presence of the PI3 kinase inhibitors wortmannin and 2-(4-morpholinyl)-8-phenyl-4 H-1-benzopyran-4-one (LY294002). Furthermore, we show that the maintenance phase of depolarizing pulse potentiation requires continued PI3 kinase activity because the application of either wortmannin or LY294002 results in a reversal to control levels of the amplitudes of mEPSCs. Finally, we demonstrate that the increase in mEPSC amplitudes is mediated by the increased expression of functional AMPA receptors (AMPARs) because the potentiation is blocked by N-ethylmaleimide, botulinum toxin A, and a variety of short-sequence peptides that disrupt the interaction of AMPAR subunits with proteins involved with the trafficking of these to the cell membrane. Our data are consistent with the notion that PI3 kinase and membrane fusion/trafficking events play a pivotal role in coordinating changes in synaptic strength, mediated by AMPA receptors, which are triggered by alterations in postsynaptic calcium concentrations whether these changes are initiated via NMDAR-dependent or NMDAR-independent routes.

Differential Reelin-Induced Enhancement of NMDA and AMPA Receptor Activity in the Adult Hippocampus

“…It has been shown that both induction and expression of LTP requires PI3K activity (Kelly and Lynch, 2000;Sanna et al, 2002;Opazo et al, 2003). PI3K is also physically associated with AMPARs and functionally coupled with AMPAR subunit trafficking during certain forms of plasticity, such as potentiation of mEPSC in response to activation of L-type calcium channels (Baxter and Wyllie, 2006) or synaptic NMDARs (Man et al, 2003). Multiple cellular processes can lead to activation of PI3K, such as activation of Src (Krymskaya et al, 2005), G-protein-coupled receptors (Shah et al, 2006), and Ca 2ϩ -calmodulin complex after NMDAR activation (Joyal et al, 1997;Man et al, 2003).…”

Leptin inhibits 4-aminopyridine– and pentylenetetrazole-induced seizures and AMPAR-mediated synaptic transmission in rodents

“…Consequently, our results raise the possibility of a postsynaptic JAK2/PI3K-dependent mechanism for the inhibition of AMPAR-mediated synaptic transmission by leptin. However, PI3K activation causes AMPAR insertion (22,23), which should result in enhanced synaptic transmission. Such a mechanism would account for some leptin concentrations enhancing long-term synaptic plasticity at excitatory synapses (21,(38)(39)(40).…”

“…In addition, leptin enhances N-methyld-aspartate receptor (NMDAR) activity by activating PI3K and MAPK (15,20,21). Leptin-induced activation of PI3K may enhance AMPA receptor (AMPAR) synaptic transmission because PI3K increases the surface expression of AMPARs (22,23). Leptin also converts short-term potentiation (STP) into long-term potentiation (LTP) (21).…”

Non-Hebbian Synaptic Plasticity Induced by Repetitive Postsynaptic Action Potentials

“…It has been reported that tetanization with a very high frequency (200 Hz) or extracellular application of tetraethylammonium, a potassium channel blocker, can cause synaptic potentiation in a VDCCdependent manner (Grover and Teyler, 1990;Aniksztejn and Ben-Ari, 1991;Huang and Malenka, 1993); however, since these induction procedures were accompanied by synaptic stimulation, factors other than Ca 2ϩ might have contributed to these forms of LTP. Efforts to induce LTP with postsynaptic depolarization alone have not been so successful: in the visual cortex, application of intracellular tetanization was reported to induce either LTP or LTD, although it is unknown how these two forms of plasticity occur in the same condition (Volgushev et al, 1994), and in the hippocampus, there has been one report of mEPSC LTP in the culture system (Baxter and Wyllie, 2006); however, more physiological experiments with acute hippocampal slices have reported only short-term potentiation so far (Kullmann et al, 1992;Huang and Malenka, 1993;Chen et al, 1998). In this study, we found a condition in which LTP is induced by postsynaptic depolarization alone, using acute hippocampal slices from adult mice.…”