A plateau potential mediated by the activation of extrasynaptic NMDA receptors in rat hippocampal CA1 pyramidal neurons

Abstract

Hippocampal pyramidal neurons express various extrasynaptic glutamate receptors. When glutamate spillover was facilitated by blocking glutamate uptake and fast synaptic transmission was blocked by antagonists of AMPA- and NMDA-type glutamate receptors and an ionotropic GABA receptor blocker, repetitive synaptic stimulation evoked a persistent membrane depolarization that consisted of an early Ca(2+)-independent component and a late Ca(2+)-dependent component. The early component, which we refer to as a plateau potential, had a half-width of 770 +/- 160 ms and a steady peak level of -9.54 +/- 3.50 mV. It was accompanied by an increase in membrane conductance, the I-V relationship of which showed a peak at -19.91 +/- 2.18 mV and reversal of the current at -4.32 +/- 2.13 mV, and was suppressed by high concentration of an NMDA receptor (NMDAR) antagonist d-APV, or an NMDAR glycine-binding site antagonist 5,7-dCK. After blocking synaptically located NMDARs using MK801, the potential was still evoked synaptically when spillover was facilitated. A sustained depolarization was evoked by iontophoretic application of glutamate in the presence or absence of a glutamate uptake blocker. This potential was not affected by Na(+) or Ca(2+) channel blockers, but was suppressed by 5,7-dCK, leaving an unspecified depolarizing potential. Iontophoresis of NMDA evoked a sustained depolarization that was blocked by a high concentration of d-APV or 5,7-dCK. The I-V relationship of the current during this potential was similar to that obtained during the synaptically induced plateau potentials. These results show that CA1 pyramidal neurons generate plateau potentials mediated most likely by activation of extrasynaptic NMDARs.

Dynamic interplay of excitatory and inhibitory coupling modes of neuronal L-type calcium channels

“…When mode 2 gating is down, LTCC activation during physiological stimuli will preferentially have excitatory effects, e.g., driving bursts and promoting EPSPs. However, during long-lasting depolarizing voltage shifts, e.g., those that are thought to occur in neurons under ischemic conditions (8) or under conditions promoting plateau potentials (12,20,38), the coupling of LTCCs to K Ca 2.x channels may be activated, potentially supporting the counteraction of excitotoxicity (39).…”

Contribution of extrasynapticN-methyl-d-aspartate and adenosine A1 receptors in the generation of dendritic glutamate-mediated plateau potentials

“…Receptor channels located outside the synaptic cleft may also contribute charge to dendritic spikes [5,[12][13][14]. Besides the afferent glutamatergic axons, glial processes may also release glutamate that contributes to the glutamate build up (glutamate threshold) required to bring a dendrite into an UP state, which in turn brings the cell body into an UP state [1,15].…”

“…This study is based on the hypothesis that both dendritic events, NMDA spikes and glutamate-mediated plateau potentials, are driven by five critical processes: (i) synchronous activation of spatially segregated presynaptic glutamatergic terminals [16], (ii) failure of nearby glial processes to clear the bulk of extracellular glutamate [5,12,13], (iii) stimulation of extrasynaptic NR2C/D receptors on spine necks and dendritic shafts by spilled-over glutamate [12,13,17,18], (iv) glutamatedependent release of adenosine from either neurons or glia, or both [19,20], and (v) activation of adenosine-sensitive dendritic K þ current, which imposes negative feedback on the amplitude and duration of dendritic depolarizations. The aforementioned five processes (i-v) synergistically contribute to the generation of local dendritic regenerative events.…”

Synaptic and extrasynaptic plasticity in glutamatergic circuits involving dentate granule cells following chronic N-methyl-d-aspartate receptor inhibition

“…Extrasynaptic NMDAR are activated following high-frequency stimulation and subsequent synaptic glutamate spillover and/or nonneuronal glutamate release. Previous reports suggest that tonic NMDAR-mediated currents activated by ambient endogenous glutamate levels elicit plateau potentials and enhanced neuronal excitability via increased excitatory input-output gain (Sah et al 1989;Suzuki et al 2008). However, other studies reported no significant effect of small-amplitude tonic NMDAR-mediated currents on neuronal excitability (Cavelier and Attwell 2005;Le Meur et al 2007).…”

“…Chronic use of these antagonists led to neuronal vacuolization, paradoxical seizure exacerbation, increased synaptic connectivity, and increased ionotropic glutamate receptor expression (Gould et al 1994;Ikonomidou et al 1999;Loscher 1998;Muir and Lees 1995;Olney et al 1989;Parsons et al 1999;Sveinbjornsdottir et al 1993;Wang and Bausch 2004). A number of newer NMDAR antagonists appear to reduce pathological overactivation while better maintaining the physiological NMDAR function required for normal brain function.…”