Seizures induce dramatic and distinctly different changes in enkephalin, dynorphin, and CCK immunoreactivities in mouse hippocampal mossy fibers

Abstract

Light microscopic immunocytochemical techniques were used to evaluate the influence of recurrent limbic seizure activity on the immunoreactivity for 3 neuropeptides--enkephalin, dynorphin, and cholecystokinin (CCK)--contained within the mouse hippocampal mossy fiber axonal system. Seizures were induced either by the placement of a small unilateral electrolytic lesion in the dentate gyrus hilus or by intraventricular injection of kainic acid. Both treatments induce epileptiform activity in hippocampus lasting several hours. Four days after either lesion placement or injection of 0.05–0.1 microgram kainic acid, immunoreactivity for all 3 peptides was altered throughout the intact mossy fiber system, bilaterally, but in distinctly different ways: enkephalin immunoreactivity (ENK-I) was dramatically elevated, dynorphin immunoreactivity was reduced, and CCK immunoreactivity (CCK- I) was either severely reduced or completely absent in the mossy fiber system. ENK-I was also clearly increased in other areas, including the lateral septum, the entorhinal cortex, and within the entorhinal (perforant path) efferents to temporal hippocampus. In contrast, the loss of CCK seemed restricted to the mossy fiber system in that immunostaining appeared normal in scattered hippocampal perikarya, within the dentate gyrus commissural system, as well as within other limbic structures. Four days after injections of 0.2 or 0.25 microgram kainic acid, mossy fiber ENK-I was greatly elevated, dynorphin immunoreactivity was reduced, but, unlike the situation with lower kainic acid doses, CCK-I was only modestly reduced in the mossy fibers and was clearly reduced in other hippocampal systems as well. These data indicate that epileptiform physiological activity differentially affects the regulation of 3 neuroactive peptides contained within the hippocampal mossy fiber system and suggest a mechanism through which seizurelike episodes can have a lasting influence on the operation of specific hippocampal circuitries.

Expression of LIM Protein GenesLmo1, Lmo2,andLmo3in Adult Mouse Hippocampus and Other Forebrain Regions: Differential Regulation by Seizure Activity

“…After seizure activity, expression levels of immediate early genes in hippocampal principal neurons increase rapidly, peak at 1-2 hr, and decline rapidly (Morgan et al, 1987;Gass et al, 1993). Over a more prolonged time course that varies from 3-6 hr to 1-3 d and in some cases longer, expression levels of numerous other genes change, including genes encoding neuropeptides, neurotrophins, and growth associated proteins (Gall, 1988;Gall and Isackson, 1989;Gall et al, 1991;Bendotti et al, 1994;Lauterborn et al, 1995). All of these genes are expressed in a cell phenotype-specific manner, show differential levels of expression in different subsets of hippocampal principal neurons, and show changes in levels of expression in some but not other neuronal subgroups after seizure activity.…”

Voltage-dependent effects of opioid peptides on hippocampal CA3 pyramidal neurons in vitro

“…By contrast, results of several studies point to a dampening effect of dynorphins or mossy fiber activation on epileptiform activity (Tortella and Holaday, 1986;Jones, 199 l), in keeping with an inhibitory action via Z, augmentation. The differential alterations of enkephalin and dynorphin levels and metabolism in hippocampus following evoked seizure activity (Gall, 1988;Hong et al, 1988) also suggest a role for hippocampal opioids in seizure-induced behaviors.…”

Activity-dependent regulation of Neu differentiation factor/neuregulin expression in rat brain

“…For example, various treatments that induce seizure cause an increase in the expression of NGF in hippocampus (4). An even more dramatic and rapid elevation of brain-derived neurotrophic factor (BDNF) mRNA was observed after limbic seizures (1).…”