Synaptic NMDA receptor activity at resting membrane potentials

Area of Science:

• Neuroscience
• Cellular and Molecular Neuroscience

Background:

• N-methyl-D-aspartate receptors (NMDARs) are critical for glutamatergic synaptic transmission in the mammalian central nervous system.
• NMDAR function is typically understood to require both glutamate/co-agonist binding and postsynaptic depolarization to overcome voltage-dependent magnesium block.

Purpose of the Study:

• To investigate NMDAR-mediated currents and calcium influx under physiological ionic conditions, particularly in the absence of significant postsynaptic depolarization.
• To re-evaluate the role of NMDARs in synaptic signaling under conditions that mimic the in vivo environment.

Main Methods:

• Synaptic currents were measured in layer 2/3 neurons of the somatosensory cortex and hippocampal CA1 neurons.
• Calcium influx was assessed using fluorescent Ca2+ indicators.
• Current clamp recordings were used to evaluate membrane potential and action potential firing thresholds.

Main Results:

• Measurable NMDAR currents were observed across all tested voltages, independent of concurrent AMPA receptor (AMPAR) depolarization.
• NMDAR currents were enhanced at negative potentials under physiological ionic conditions compared to standard slice conditions.
• Calcium influx through NMDARs was detected even when AMPARs were blocked, and NMDARs contributed to excitatory postsynaptic potentials (EPSPs) at resting membrane potentials.

Conclusions:

• NMDARs contribute significantly to synaptic currents and calcium influx even without postsynaptic depolarization, particularly under physiological ionic conditions.
• These findings challenge the traditional view of NMDARs solely as coincidence detectors requiring strong depolarization.
• The results highlight a more pervasive role for NMDARs in basal synaptic transmission and neuronal excitability.