Recent studies have demonstrated that the regulation of
neuropeptide expression in forebrain neurons is responsive to external influences including changes in physiological activity. This has been demonstrated most clearly in studies of hippocampus where the synthesis and resting levels of several
neuropeptides, localized within well-characterized components of hippocampal circuitry, have been shown to be selectively influenced by seizure activity. In studies described here, we examined the influence of recurrent limbic
seizures on the expression of
enkephalin,
dynorphin,
cholecystokinin, and
neuropeptide Y (NPY) in rat and mouse hippocampus using immunohistochemical, in situ hybridization and blot hybridization techniques. The data demonstrate that
seizures differentially influence the expression of each
peptide as a part of a broader cascade of changes in genomic expression within individual hippocampal neurons. In particular,
seizures increase
preproenkephalin mRNA and
enkephalin peptide but decrease
dynorphin peptide in the dentate gyrus granule cell/mossy fiber system. Seizure-induced decreases in the concentration of
preprodynorphin mRNA in the granule cells have been reported by others. Immunoreactivity for CCK, which is codistributed with the
opioid peptides in the mossy fiber system of mouse, is also dramatically reduced in the granule cell axons by seizure. Recurrent
seizures induce two temporally distinct changes in NPY expression in hippocampus. First, there is an increase in hybridization to preproNPY
mRNA within scattered, probable local circuit neurons in all subfields. This is followed by the seemingly novel appearance of preproNPY
mRNA within the dentate gyrus granule cells and pyramidal cells of field CA1. Clues about mechanisms of
neuropeptide regulation have come from observations of other, more rapid, transcriptional events induced by seizure. Most notably, our results and those of others demonstrate that
seizures increase the expression of messenger RNAs from immediate-early genes (c-fos, c-jun, and NGFI-A) which encode
proteins that may mediate
neuropeptide gene regulation. In addition,
mRNA for
nerve growth factor is dramatically increased in the dentate gyrus granule cells by seizure; increased production of this trophic factor might mediate the more delayed changes in genomic expression and growth responses observed to occur in hippocampus and other forebrain areas following seizure activity.