HIPPOCAMPAL AMPA AND NMDA MESSENGER-RNA LEVELS CORRELATE WITH ABERRANT FASCIA-DENTATA MOSSY FIBER SPROUTING IN THE PILOCARPINE MODEL OF SPONTANEOUS LIMBIC EPILEPSY

There is considerable controversy whether aberrant fascia dentata (FD) mossy fiber sprouting is an epiphenomena related to neuronal loss or a pathologic abnormality responsible for spontaneous limbic seizures. If mossy fiber sprouting contributes to seizures, then reorganized axo n circuits should alter postsynaptic glutamate receptor properties, In the pilocarpine-status rat model, this study determined if changes in alpha amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) and n-me thyl-D-aspartic acid (NMDA) receptor subunit mRNA levels correlated wi th mossy fiber sprouting. Sprague-Dawley rats were injected with piloc arpine (320 mg/kg; i.p.) and maintained in status epilepticus for 6 to 8 hours (pilocarpine-status). Rats were killed during the: (1) latent phase after neuronal loss but before spontaneous limbic seizures (day 11 poststatus; n = 7); (2) early seizure phase after their first seiz ures (day 25; n = 7); and (3) chronic seizure phase after many seizure s (day 85; n = 9). Hippocampi were studied for neuron counts, inner mo lecular layer (IML) neo-Timm's staining, and GluR1-3 and NMDAR1-2b mRN A levels. Compared with controls, pilocarpine-status rats in the: (1) latent phase showed increased FD GluR3, NMDAR1, and NMDAR2b; greater C A4 and CA1 NMDAR1; and decreased subiculum GluR1 hybridization densiti es; (2) early seizure phase showed increased FD GluR3, increased CA1 N MDAR1, and decreased subiculum NMDAR2b densities; and (3) chronic seiz ure phase showed increased FD GluR2; increased FD and CA4 GluR3; decre ased CA1 GluR2; and decreased subiculum GluR1, GluR2, NMDAR1, and NMDA R2b levels, In multivariate analyses, greater IML neo-Timm's staining: (1) positively correlated with FD GluR3 and NMDAR1 and (2) negatively correlated with CA1 and subiculum GluR1 and GluR2 mRNA levels. These results indicate that: (1) hippocampal AMPA and NMDA receptor subunit mRNA levels changed as rats progressed from the latent to chronic seiz ure phase and (2) certain subunit alterations correlated with mossy fi ber sprouting, Our findings support the hypothesis that aberrant axon circuitry alters postsynaptic hippocampal glutamate receptor subunit s toichiometry; this may contribute to limbic epileptogenesis. J. Neuros ci. Res. 54:734-753, 1998. (C) 1998 Wiley-Liss, Inc.