MOLECULAR AND CELLULAR NEUROSCIENCES 3,79-87 (19%) Biphasic Response of Hippocampal Dynorphin Expression following Recurrent Limbic Seizure’ JEFFREY D. WHITE,**' GARRET L.YouNT,* JULIE ~.LAUTERBORN,~ JAMES E. KRAUSE,$ AND CHRISTINE M. GALL? Division of Endocrinology, Department of Medicine and *Department of Neurobiology and Behavior, SUNY Stony Brook, Stony Brook, New York 11794, tDepartment of Anutomy and Neurobiology, University of California Irvine, Irvine, California 92717; and SDepartment of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110 Received for publication October 2, 1991 The opioid peptide dynorphin (DYN) is expressed nor- mally at high levels in dentate gyrus granule cells in hip- pocampus and in neurons in entorhinal and neocortex. In the present study, ribonuclease protection and in situ hybridization analyses were used to examine preproDYN mRNA expression in hippocampus and neocortex fol- lowing recurrent limbic seizure induced by a unilateral electrolytic lesion of the dentate gyrus hilus. In this par- adigm, electrographic seizures within hippocampus recur intermittently from 1.6 to 12 h following the hilus lesion (HL). Solution hybridization-ribonuclease protection analysis of preproDYN mRNA levels in hippocampal dentate gyrus/CAl samples from rats sacrificed 6 and 12 h following HL revealed an approximate 6-fold increase above control values at both times. PreproDYN mRNA levels returned toward control values by 24 h post-HL, were suppressed up to lo-fold below control values at 48 and 96 h post-HL, and then returned to control levels by 10 days post-HL. In situ hybridization analyses con- firmed the biphasic nature of seizure-induced changes in preproDYN expression specifically within dentate gyrus granule cells. Additionally, these latter studies demon- strated that seizures induce expression of preproDYN mRNA in a small population of neurons within stratum pyramidale CAl. Transient increases in preproDYN mRNA were also detected in subiculum and entorhinal cortex. However, in neocortex hybridization of prepro- DYN mRNA remained constant through 96 h post-HL. These findings of biphasic seizure-induced alterations in preproDYN mRNA expression can be contrasted with previously described changes in gene expression follow- ing limbic seizure activity and suggest that different cellular mechanisms regulate expression of colocalized hippocampal neuropeptides such as dynorphin, Met- enkephalin, and neuropeptide Y. @ 1992 Academic m, IILC. 1 These data were presented in part at the 20th Annual Meeting of the Society for Neuroscience, St. Louis, MO. 2 To whom correspondence should be addressed. 79 INTRODUCTION A variety of recent studies have demonstrated that neuronal gene expression is significantly affected by transsynaptic impulse activity. Thus, adult neurons dis- play remarkable plasticity with respect to the complement of neurotransmitters and neuromodulators that they are capable of expressing. The hippocampus has proven to be a useful model system in studies investigating the re- lationship of transsynaptic activity and gene expression due to its extreme seizure susceptibility. With seizures, an experimental paradigm is established in which large numbers of neurons are activated sychronously and thereby permit biochemical analyses to be performed. The hippocampus holds an additional appeal because of its well-delineated cytoarchitecture and electrophysiological connections. For example, the opioid peptides dynorphin (DYN) and enkephalin (ENK) are expressed differentially in hippocampal dentate gyrus granule cells in that DYN is expressed at high levels in the basal state while basal expression of ENK is low (1,Z). However, following hilus lesion (HL)-induced recurrent limbic seizures, all granule cells also express preproENK mRNA and ENK peptide at high levels (3, 4). This induction of ENK expression is not confined to HL-induced seizures in that seizure activity induced by electroconvulsive shock (5), kainic acid (6,7), pentylenetetrazol (8), or kindling (9) have all been demonstrated to induce a significant but transient in- crease in preproENK mRNA levels or ENK-like immu- noreactivity. Conversely, hippocampal DYN expression has been reported generally to be inhibited by seizure ac- tivity. Thus, 24 h following prepiriform cortex (9, 10) or hippocampal (11) kindling or repeated electroconvulsive shock (ECS) (5), preproDYN mRNA and DYN peptide levels are reduced. However, at shorter times following a single ECS preproDYN mRNA levels are transiently in- creased (5). Altered DYN expression following seizure does not appear to be confined to rodents in that DYN immunostaining in human hippocampus has been shown 1044-7431/92 $3.00 Copyright 0 1992 by Academic Press, Inc. All rights of reproduction in any form rswmd.