Generation and propagation of 4-AP-induced epileptiform activity in neonatal intact limbic structures in vitro

We examined the generation, propagation and pharmacology of 4-aminopyridine (4-AP)-induced epileptiform activity (EA) in the intact interconnected lim bic structure of the newborn (P0-7) rat in vitro. Whole-cell recordings of CA3 pyramidal cells and multisite field potential recordings in CA3, CA1, d entate gyrus, and lateral and medial entorhinal cortex revealed 4-AP-induce d EA as early as P0-1. At this age, EA was initiated in the CA3 region and propagated to CA1, but not to the entorhinal cortex. Starting from P3-4, EA propagated from CA3 to the entorhinal cortex. Along the CA3 septo-temporal axis, EA arose predominantly from the septal pole and spread towards the t emporal site. Whereas the onset of 4-AP-induced EA decreased with age from 21.2 +/- 1.6 min at P0-1 to 4.7 +/- 0.63 min at P6-7, the seizure duration increased in the same age groups from 98 +/- 14 s to 269.4 +/- 85.9 s, resp ectively. The EA was blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) but not by dl-2-amino-5-phosphonovaleric acid (APV), (+)-MK-801 hydrogen m aleate (MK-801) or (+/-)-alpha-methyl-4-carboxyphenylglycine (MCPG), sugges ting that they were mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolep ropionate (AMPA)/kainate receptor activation. We conclude that: (i) the sep tal pole of the hippocampal CA3 region plays a central role in the generati on of EA in the neonatal limbic system; and (ii) AMPA/kainate receptor-medi ated EA can be generated in CA3 already at birth. Therefore, the recurrent collateral synapses and circuits required for the generation of EA are deve loped earlier than previously suggested on the basis of studies on hippocam pal slices.