Slow afterhyperpolarization governs the development of NMDA receptor-dependent afterdepolarization in CA1 pyramidal neurons during synaptic stimulation

J Neurophysiol. 2004 Oct;92(4):2346-56. doi: 10.1152/jn.00977.2003. Epub 2004 Jun 9.

Abstract

CA1 pyramidal neurons from animals that have acquired a hippocampus-dependent task show a reduced slow postburst afterhyperpolarization (sAHP). To understand the functional significance of this change, we examined and characterized the sAHP activated by different patterns of synaptic stimuli and its impact on postsynaptic signal integration. Whole cell current-clamp recordings were performed on rat CA1 pyramidal neurons, and trains of stratum radiatum stimuli varying in duration, frequency, and intensity were used to activate the AHP. At -68 mV, a short train of subthreshold stimuli (20-150 Hz) generated only the medium AHP. In contrast, just two suprathreshold stimuli >50 Hz triggered a prominent sAHP sensitive to bath-applications of isoproterenol, carbachol, or intracellularly applied BAPTA, suggesting that the underlying current is the Ca2+-activated K+ current, the sIAHP. The sAHP magnitude was positively related to stimulus train duration and frequency, consistent with its dependence on intracellular Ca2+ accumulation for activation. About 20% of neurons recorded did not have a sAHP. In response to high-frequency suprathreshold stimuli, these neurons developed a pronounced afterdepolarization (ADP) and multiple action potential firing. The ADP magnitude increased with successive stimuli and was positively related to stimulus intensity and frequency. It was sensitive to bath-applications of thapsigargin and nitrendipine, and abolished by d-AP5, indicating that it is supported by intracellular Ca2+ release, the L-type Ca2+ influx, and N-methyl-D-aspartate (NMDA) receptor-mediated influx. In the presence of D-AP5, we were unable to trigger an ADP with maximal stimulus intensity. Pharmacologically eliminating the sAHP allowed neurons to develop an ADP with the original stimulus train. We propose that the slow AHP acts to facilitate Mg2+ re-block of the activated NMDA receptors, thereby reducing temporal summation and preventing an NMDA receptor-dependent ADP during intense synaptic events. Neuromodulation of the sAHP may thus affect information throughput and regulate NMDA receptor-mediated plasticity.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 2-Amino-5-phosphonovalerate / pharmacology
  • 6-Cyano-7-nitroquinoxaline-2,3-dione / pharmacology
  • Action Potentials / drug effects
  • Animals
  • Calcium Channels, L-Type / drug effects
  • Calcium Channels, L-Type / physiology
  • Electric Stimulation
  • Electrophysiology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Excitatory Postsynaptic Potentials / physiology
  • Hippocampus / cytology
  • Hippocampus / physiology*
  • In Vitro Techniques
  • Male
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Neuronal Plasticity / drug effects
  • Patch-Clamp Techniques
  • Pyramidal Cells / drug effects
  • Pyramidal Cells / physiology*
  • Pyramidal Cells / ultrastructure
  • Rats
  • Rats, Inbred F344
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Synapses / drug effects
  • Synapses / physiology*
  • Synapses / ultrastructure

Substances

  • Calcium Channels, L-Type
  • Excitatory Amino Acid Antagonists
  • Receptors, N-Methyl-D-Aspartate
  • 6-Cyano-7-nitroquinoxaline-2,3-dione
  • 2-Amino-5-phosphonovalerate