4-Aminopyridine-induced spreading depression episodes in immature hippocampus: developmental and pharmacological characteristics

Neuroscience. 1993 Jul;55(1):57-68. doi: 10.1016/0306-4522(93)90454-n.


Spontaneous spreading depression episodes were studied in CA1 and CA3 areas of immature hippocampal slices (two to 30 days postnatally) during 4-aminopyridine (50 microM) perfusion. Spreading depression occurred in the CA3 area of 34% of all slices tested (two to 30 days postnatally). The duration and frequency of the spreading depression field potentials changed with development. In the CA3 area, their duration decreased from 169 +/- 22 s (n = 17, postnatal days to to 10) to 55 +/- 7 s (n = 10, postnatal days 21-30), their rate of occurrence increased from four episodes per hour (0.0011 +/- 0.0001 Hz, n = 11, postnatal days two to 10) to 6.5 episodes per hour (0.0018 +/- 0.0003 Hz, n = 8, postnatal days 21-30), while their amplitude remained stable (10-30 mV). Spreading depression d.c. potential shift originated closer to CA1 than CA3. Furthermore, spreading depression field potentials had greater magnitude (amplitude and duration) in CA1. Spreading depressions were reversibly blocked by the N-methyl-D-aspartate receptor antagonist 3,3-(2-carboxy-piperazine-4-yl)-propyl-1-phosphonate (CPP, 1-5 microM, n = 15), but were not affected by 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX, 2-5 microns, n = 11), which is a non-N-methyl-D-aspartate receptor antagonist. The GABAA receptor antagonist bicuculline methiodide (3-10 microM) initially favored and then blocked spreading depression in 79% of the slices tested (n = 16). In addition, bicuculline impaired spreading depression propagation from CA1 to CA3. 4-Aminopyridine also induced the appearance of other types of spontaneous activity, such as ictal and interictal-like epileptiform discharges. The effects of 3,3-(2-carboxy-piperazine-4-yl)-propyl-1-phosphonate, 6-cyano-7-nitro-quinoxaline-2,3-dione and bicuculline on epileptiform activity were opposite to those on spreading depression. Our findings demonstrate that spreading depression can occur as early as two days postnatally and that the characteristics of this phenomenon change with maturation. These results also indicate that 4-aminopyridine-induced spreading depression episodes and epileptiform activity are mediated by the activation of different types of excitatory amino acid receptors. Finally, spreading depression is influenced by blockade of the GABAA receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Aminopyridine / toxicity*
  • 6-Cyano-7-nitroquinoxaline-2,3-dione
  • Animals
  • Bicuculline / pharmacology
  • Cortical Spreading Depression / drug effects*
  • Cortical Spreading Depression / physiology
  • GABA-A Receptor Antagonists
  • Hippocampus / drug effects*
  • Hippocampus / growth & development
  • Hippocampus / physiopathology
  • Piperazines / pharmacology
  • Quinoxalines / pharmacology
  • Rats
  • Rats, Sprague-Dawley / growth & development
  • Receptors, GABA-A / drug effects
  • Receptors, GABA-A / physiology
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Receptors, N-Methyl-D-Aspartate / physiology
  • gamma-Aminobutyric Acid / physiology


  • GABA-A Receptor Antagonists
  • Piperazines
  • Quinoxalines
  • Receptors, GABA-A
  • Receptors, N-Methyl-D-Aspartate
  • gamma-Aminobutyric Acid
  • 6-Cyano-7-nitroquinoxaline-2,3-dione
  • 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid
  • 4-Aminopyridine
  • Bicuculline