NEURON LOSS, MOSSY FIBER SPROUTING, AND INTERICTAL SPIKES AFTER INTRAHIPPOCAMPAL KAINATE IN DEVELOPING RATS

This study determined neuron losses, messy fiber sprouting, and interi ctal spike frequencies in adult rats following intrahippocampal kainic acid (KA) injections during postnatal (PN) development. KA (0.4 mu g/ 0.2 mu 1; n = 64) was injected into one hippocampus and saline into th e contralateral side between PN 7 to 30 days. Animals were sacrificed 28 to 256 days later, along with age-matched naive animals (controls; n = 20). Hippocampi were studied for: (1) Fascia dentata granule cell, hilar, and CA3c neuron counts; (2) neo-Timm's stained supragranular m essy fiber sprouting; and (3) hippocampal and intracerebral interictal spike densities (n = 13). Messy fiber sprouting was quantified as the gray value differences between the inner and outer molecular layer. S tatistically significant results (p < 0.05) showed the following: (I) Compared to controls, CA3c and hilar neuron counts were reduced in KA- hippocampi with injections at PN 7-10 and PN 12-14 respectively and co unts decreased with older PN injections. Granule cell densities on the KA-side and saline-injected hippocampi were not reduced compared to c ontrols. (2) In adult rats, supragranular messy fiber sprouting was ob served in 2 of 7 PN 7 injected animals. Compared to controls, increase d gray value differences, indicating messy fiber sprouting, were found on the KA-side beginning with injuries at PN 12-14 and increasing wit h older PN injections. On the saline-side only PN 30 animals showed mi nimal sprouting. (3) Messy fiber sprouting progressively increased on the KA-side with longer survivals in rats injured after PN 15. Sprouti ng correlated positively with later PN injections and longer post-inje ction survival intervals, and not with reduced hilar or CA3c neuron co unts. (4) On the KA-side, messy fiber gray value differences correlate d positively with in vivo intrahippocampal interictal spike densities. These results indicate that during postnatal rat development intrahip pocampal kainate excitotoxicity can occur as early as PN 7 and increas es with older ages at injection. This rat model reproduces many of the pathologic, behavioral, and electrophysiologic features of human mesi al temporal lobe epilepsy, and supports the hypothesis that hippocampa l sclerosis can be the consequence of focal injury during early postna tal development that progressively evolves into a pathologic and epile ptic focus.