Kinetics of Mg(2+) unblock of NMDA receptors: implications for spike-timing dependent synaptic plasticity Journal Article


Author(s): Kampa, Bjorn M; Clements, John; Jonas, Peter; Stuart, Greg J
Article Title: Kinetics of Mg(2+) unblock of NMDA receptors: implications for spike-timing dependent synaptic plasticity
Affiliation
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.
Keywords: Animals; Rats; Kinetics; Markov Chains; Pyramidal Cells/physiology; Models, Neurological; Rats, Wistar; Neuronal Plasticity/physiology; Action Potentials/drug effects/*physiology; Cerebral Cortex/cytology; Excitatory Postsynaptic Potentials/drug effects/physiology; Glutamic Acid/pharmacology; Ion Channel Gating/drug effects/*physiology; Magnesium/pharmacology; Receptors, N-Methyl-D-Aspartate/metabolism
Journal Title: Journal of Physiology
Volume: 556
Issue Pt 2
ISSN: 1469-7793
Publisher: Wiley-Blackwell  
Publication Place: England
Date Published: 2004-01-01
Start Page: 337
End Page: 45
URL:
DOI: 10.1113/jphysiol.2003.058842
Open access: yes (repository)