NMDA receptors and L-type voltage-gated Ca²⁺ channels mediate the expression of bidirectional homeostatic intrinsic plasticity in cultured hippocampal neurons

Neuroscience. 2014 Sep 26;277:610-23. doi: 10.1016/j.neuroscience.2014.07.038. Epub 2014 Jul 31.


Homeostatic plasticity is engaged when neurons need to stabilize their synaptic strength and excitability in response to acute or prolonged destabilizing changes in global activity. Compared to the extensive studies investigating the molecular mechanisms for homeostatic synaptic plasticity, the mechanism underlying homeostatic intrinsic plasticity is largely unknown. Through whole-cell patch-clamp recording in low-density cultures of dissociated hippocampal neurons, we demonstrate here that prolonged activity blockade induced by the sodium channel blocker tetrodotoxin (TTX) leads to increased action potential firing rates. Conversely, prolonged activity enhancement induced by the A-type gamma-aminobutyric acid receptor antagonist bicuculline (BC) results in decreased firing rates. Prolonged activity enhancement also enhanced potassium (K(+)) current through Kv1 channels, suggesting that changes in K(+) current, in part, mediate stabilization of hippocampal neuronal excitability upon prolonged activity elevation. In contrast to the previous reports showing that L-type voltage-gated calcium (Ca(2+)) channels solely mediate homeostatic regulation of excitatory synaptic strength (Ibata et al., 2008; Goold and Nicoll, 2010), inhibition of N-Methyl-d-aspartate (NMDA) receptors alone mimics the elevation in firing frequency driven by prolonged TTX application, while the decrease in firing rates induced by prolonged BC treatment involves the activity of NMDA receptors and L-type voltage-gated Ca(2+) channels. These results collectively provide strong evidence that alterations in Ca(2+) influx through NMDA receptors and L-type voltage-gated Ca(2+) channels mediate homeostatic intrinsic plasticity in hippocampal neurons in response to prolonged activity changes.

Keywords: L-type voltage-gated Ca(2+) channel; NMDA receptor; action potential; hippocampus; homeostatic intrinsic plasticity; potassium channel.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology
  • Animals
  • Bicuculline / pharmacology
  • Calcium / metabolism
  • Calcium Channels, L-Type / metabolism*
  • Cells, Cultured
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology
  • GABA-A Receptor Antagonists / pharmacology
  • Hippocampus / drug effects
  • Hippocampus / physiology*
  • Miniature Postsynaptic Potentials / drug effects
  • Miniature Postsynaptic Potentials / physiology
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / physiology*
  • Neurons / drug effects
  • Neurons / physiology*
  • Patch-Clamp Techniques
  • Potassium / metabolism
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Shaker Superfamily of Potassium Channels / metabolism
  • Sodium Channel Blockers / pharmacology
  • Tetrodotoxin / pharmacology


  • Calcium Channels, L-Type
  • GABA-A Receptor Antagonists
  • Receptors, N-Methyl-D-Aspartate
  • Shaker Superfamily of Potassium Channels
  • Sodium Channel Blockers
  • Tetrodotoxin
  • Potassium
  • Calcium
  • Bicuculline