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Kinetics of Mg 2+ unblock of NMDA receptors: implications for spike‐timing dependent synaptic plasticity
Author(s) -
Kampa Björn M.,
Clements John,
Jonas Peter,
Stuart Greg J.
Publication year - 2004
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2003.058842
Subject(s) - depolarization , nmda receptor , glutamate receptor , biophysics , neuroscience , chemistry , time constant , pulse (music) , synaptic plasticity , receptor , biology , physics , biochemistry , engineering , electrical engineering , optics , detector
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 ∼100 μs) and slower components (time constants 4 and ∼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.