Kinetics of Mg²⁺ unblock of NMDA receptors: implications for spike‐timing dependent synaptic plasticity

Abstract

The time course of Mg(2+) block and unblock of NMDA receptors (NMDARs) determines the extent they are activated by depolarization. Here, we directly measure the rate of NMDAR channel opening in response to depolarizations at different times after brief (1 ms) and sustained (4.6 s) applications of glutamate to nucleated patches from neocortical pyramidal neurons. The kinetics of Mg(2+) unblock were found to be non-instantaneous and complex, consisting of a prominent fast component (time constant approximately 100 micros) and slower components (time constants 4 and approximately 300 ms), the relative amplitudes of which depended on the timing of the depolarizing pulse. Fitting a kinetic model to these data indicated that Mg(2+) not only blocks the NMDAR channel, but reduces both the open probability and affinity for glutamate, while enhancing desensitization. These effects slow the rate of NMDAR channel opening in response to depolarization in a time-dependent manner such that the slower components of Mg(2+) unblock are enhanced during depolarizations at later times after glutamate application. One physiological consequence of this is that brief depolarizations occurring earlier in time after glutamate application are better able to open NMDAR channels. This finding has important implications for spike-timing-dependent synaptic plasticity (STDP), where the precise (millisecond) timing of action potentials relative to synaptic inputs determines the magnitude and sign of changes in synaptic strength. Indeed, we find that STDP timing curves of NMDAR channel activation elicited by realistic dendritic action potential waveforms are narrower than expected assuming instantaneous Mg(2+) unblock, indicating that slow Mg(2+) unblock of NMDAR channels makes the STDP timing window more precise.

Dendritic Compartment and Neuronal Output Mode Determine Pathway-Specific Long-Term Potentiation in the Piriform Cortex

“…We observed a similar situation in apical dendrites of layer 2 pyramidal cells in the piriform cortex: the pharmacological block of A-type K ϩ conductances resulted in a significant increase in the amplitude of bAP-mediated Ca 2ϩ signals in layer 1a, and we demonstrated that expression levels of Kv4.2 and Kv4.3 (the subunits underlying dendritic A-type conductances) are higher in layer 1a than in layer 1b. Finally, failure of voltage propagation is documented using the coincidence detection mechanism of the NMDAR as a reporter (Kampa et al, 2004;Nevian and Sakmann, 2004). This second readout of dendritic depolarization is of special importance, because the distance-dependent amplitude of bAP-mediated Ca 2ϩ signals may be affected by factors different from the spread of the voltage signal.…”

“…LTP can be induced in pyramidal cells when the presynaptic firing is followed by postsynaptic spiking at a time interval of up to 50 ms Markram et al, 1997;Bi and Poo, 1998;Debanne et al, 1998) (for review, see Kampa et al, 2007). During LTP induction, bAPs can boost the spine Ca 2ϩ response by depolarization-mediated release of the NMDAR Mg 2ϩ block (Koester and Sakmann, 1998;Kampa et al, 2004;Sakmann, 2004, 2006). The integration of presynaptic and postsynaptic firing in spines in the layer 1a and layer 1b dendritic compartments was analyzed.…”

Amantadine Inhibits NMDA Receptors by Accelerating Channel Closure during Channel Block

“…The test is based on the observation that, after block of NMDA receptor channels by extracellular Mg 2ϩ (Mg ments. Kinetic models were used to explore possible explanations for these observations (Kampa et al, 2004;Vargas-Caballero and Robinson, 2004). It was found that slow components of unblock are expected if blocker binding increases the occupation of channel closed states.…”

The Properties and Implications of NMDA Spikes in Neocortical Pyramidal Cells

“…Because pyramid-pyramid synapses in cortex generally exhibit net paired-pulse depression (Thomson, 2003), revision of this work to incorporate synapse dynamics will increase the predicted NMDA conductance required for production of NMDA spikes. Also not accounted for here is the recently described slow component of the voltage-dependent unblock of the NMDA receptor (Vargas-Caballero and Robinson, 2003; Kampa et al, 2004), the effect of which would also be to reduce the amount of NMDA conductance available to drive the NMDA spike event. Thus, at least with respect to more accurate biophysical models of release dynamics and NMDA unblock, the conclusions presented here regarding the predicted magnitude of the average NMDA conductance per synapse and the NMDA/AMPA ratio may be conservative.…”