30 BRES 16774 Brain Research, 554 (1991) 30-37 © 1991 Elsevier Science Publishers B.V. 0006-8993/91/$03.50 ADONIS (1006899391167741. Hippocampal grafts into the intact brain induce epileptic patterns Gy6rgy Buzs~iki, Eliezer Masliah, Lan S. Chen, Zsolt Horv~ith, Robert Terry and Fred H. Gage Department of Neurosciences M-024, Universtiy of California at San Diego, San Diego, CA 92093 (U.S.A.) (Accepted 5 February 1991) Key words: Transplantation; Hippocampus; Epilepsy', Population burst; Interictal spike; Kindling Spontanenous hippocampal EEG activity and evoked field potentials were investigated in intact rats and in animals with fetal hippocampal grafts. Pieces of hippocampal grafts, derived from 15- to 16-day-old fetuses, were used to prepare cell suspensions and grafted directly into the intact hippocampus. Control animals received suspension grafts of the cerebellum derived from fetuses of identical age. Host hippoeampal electrical patterns were monitored with chronic single electrodes or with a 16-microelectrode probe from 7 to 10 months after grafting. In contrast to previously reported high survival rates of fetal grafts in studies with damage to the host brain prior to grafting, survival of both hippocampal (60%) and cerebellar grafts (20%) was very poor in the intact hippocampus. In animals with cerebellar transplants or without surviving grafted neurons the electrical activity of the host hippocampus was indistinguishable from normal controls. In rats with hippocampal grafts short duration, large amplitude EEG spikes (up to 10 mV) were recorded, predominantly during immobility. When the EEG spikes (putative interictal spikes) were of large amplitude and contained population spikes, test evoked responses delivered to the perforant path were suppressed after the spontaneous events. In contrast, evoked responses were facilitated by interictal spikes without population spikes. The threshold of electrically induced afterdischarges did not differ significantly between groups of intact rats and animals with or without hippocampal grafts. However, in three rats with hippocampal grafts the evoked afterdischarges were associated with behavioral seizures. In two of these rats spontaneously occurring seizures were also observed. Synaptophysin-immunoreactivity demonstrated growth of the host mossy fibers into the graft. These findings demonstrate that grafting of fetal hippocampal tissue into the intact host hippocampus significantly elevates the excitability of the recipient brain to the extent of epileptic discharges. We suggest that spontaneous behavioral convulsions occurred because the grafted hippocampus served as an epileptic focus that kindled the host brain by repeated seizure induction. INTRODUCTION Research during the last several years has provided support for the idea that fetal nervous tissue can survive in the adult mammalian brain and can modify the function and behavior of the host (cf. refs. 3,32). Grafts of fetal hippocampal premordia have been frequently used to study the anatomical connections and physiolog- ical changes in the damaged neuronal circuitry and to investigate the behavioral consequences of transplan- tation6-9,12.15,20-24,26.29-31.34.36-3S Physiological studies of the grafted hippocampus into the damaged nervous system have indicated that the transplanted hippocampus is hyperexcitable and can display both spontaneous and evoked seizure activity6' 9,12,20,21. Since these studies were carried out on animals with previous damage of the host nervous system 1x'17, it could not be definitely decided whether the increased excitability of the grafted tissue was a genuine feature of the newly developing neuronal circuitry or a result of a long-term host-graft interaction. Since fetal neuronal tissue is generally transplanted into a surgically damaged or epilepsy-prone host brain, it can be argued that the grafted tissue acquires the epileptic patterns from the host during its development. In the present study hippocampal or cerebellar tissue was grafted into the intact nervous system and the electrical patterns of the host hippocampus were inves- tigated several months after transplantation. Animals with cell suspension grafts of the fetal hippocampus developed large amplitude EEG spikes and electroen- cephalographic seizures, and some animals exhibited behavioral convulsions. MATERIALS AND METHODS Animals and surgery These experiments were carried out on 21 female rats of the Sprague-Dawley strain. Neuronal grafting (n = 15) was conducted at 2 months of age and physiological testing began 7-10 months after transplantation. The rats were anesthetized with a mixture of ketamine (100 mg/kg), xylazine (5.2 mg/kg) and aeepromazine (1 mg/kg). Fetal hippocampal grafts or cerebellar grafts were obtained from 15 to 16- day-old embryos by dissection. The dissected pieces Correspondence: G. Buzsaki, Center for Molecular and Behavioral Neuroscience, Rutgers University, 195 University Avenue, Newark, NJ 07102, U.S.A. Fax: (1) (201) 648 1272.