Pattern-Dependent Role of NMDA Receptors in Action Potential Generation: Consequences on Extracellular Signal-Regulated Kinase Activation

Abstract

Synaptic long-term potentiation is maintained through gene transcription, but how the nucleus is recruited remains controversial. Activation of extracellular signal-regulated kinases (ERKs) 1 and 2 with synaptic stimulation has been shown to require NMDA receptors (NMDARs), yet stimulation intensities sufficient to recruit action potentials (APs) also appear to be required. This has led us to ask the question of whether NMDARs are necessary for AP generation as they relate to ERK activation. To test this, we examined the effects of NMDAR blockade on APs induced with synaptic stimulation using whole-cell current-clamp recordings from CA1 pyramidal cells in hippocampal slices. NMDAR antagonists were found to potently inhibit APs generated with 5 and 100 Hz synaptic stimulation. Blockade of APs and ERK activation could be overcome with the addition of the GABA A antagonist bicuculline, indicating that APs are sufficient to activate signals such as ERK in the nucleus and throughout the neuron in the continued presence of NMDAR antagonists. Interestingly, no effects of the NMDAR antagonists were observed when theta-burst stimulation (TBS) was used. This resistance to the antagonists is conferred by temporal summation during the bursts. These results clarify findings from a previous study showing that ERK activation induced with TBS is resistant to 2-amino-5-phosphonovalerate, in contrast to that induced with 5 or 100 Hz stimulation, which is sensitive. By showing that NMDAR blockade inhibits AP generation, we demonstrate that a major role that NMDARs play in cell-wide and nuclear ERK activation is through their contribution to action potential generation.

Synaptic Plasticity (and the Lack Thereof) in Hippocampal CA2 Neurons

“…Thus, if TREK-1 or other two-pore domain channel-mediated current leak is the factor limiting LTP and/or LTD induction in CA2, it is likely to be doing so in the dendrites or by regulating other voltagedependent channels and not by influencing somatic action potentials. The total number of action potentials could, however, impact ERK activation in that the two are intimately linked (Zhao et al, 2005). Active and passive dendritic currents also remain a possible site of plasticity regulation in CA2, but additional work using recordings from dendrites will be required to rule out or support this hypothesis.…”

Macromolecular transport in synapse to nucleus communication

“…Their arrival at the nucleus enables the local activation of calcium-dependent pathways connected to gene transcription. This mode of synapse to nucleus communication has been intensively studied for excitatory synapses and calcium influx generated by activation of synaptic NMDA receptors, L-type calcium channels, or intracellular calcium release [17][18][19][20]. The resulting action potentials generated at the initial axon segment may propagate retrogradely in the soma, and spread into dendrites [21].…”

Effects of Chronic Introduction of Antidepressants on NMDA-Induced Damage to Neurons of the Rat Hippocampus and Cerebral Cortex

“…Under conditions of the action of NMDA on neurons, activation of voltage-dependent calcium channels can be observed [27]. Thus, it seems quite possible that the NMDA-induced rise in the intraneuronal Са 2+ concentration is partly related to the increase in the conductance of such calcium channels.…”