Exp Brain Res (1991) 84:529-537 Exp.erimental BrainResearch 9 Springer-Verlag 1991 Inhibition in postischemic rat hippocampus: GABA receptors, GABA release, and inhibitory postsynaptic potentials F.F. Johansen 1, T. Christensen a, M.S. Jensen 2, E. Valente ~, C.V. Jensen a, T. Nathan 2, J.D.C. Lambert 2, and N.H. Diemer 1 1 PharmaBiotec Research Center, Cerebral Ischemia Research Group, Institute of Neuropathology, University of Copenhagen, 11 Frederik V's vej, DK 2100 Copenhagen, Denmark 2 Institute of Physiology, University of Aarhus, DK-8000 Aarhus C, Denmark Received February 1, 1990 / Accepted November 26, 1990 Summary. We have investigated the GABAergic system in rat hippocampus at 1 hour and up to 21 days following 20 min of global cerebral ischemia. Distribution of 3H-GABA (in excess of unlabeled baclofen) and 3H-Ro-15-1788 (benzodiazepine antagonist) binding sites in hippocampus was studied utilizing quantitative autoradiography. The 3H-GABA binding was un- changed (p > 0.01) after ischemia, whereas the 3H-Ro-15-1788 binding decreased significantly (p<0.01) in all hippocampal subfields 1-21 days after ischemia. Using microdialysis in CA1, we found that K+-stimulated GABA release at 1 hour and 1 day after ischemia was unchanged (p>0.01) in comparison to preischemic controls. Electrophysiological recordings were made from CA1 of hippocampal slices prepared from rats sacrificed 1 hour, 1 day and 2 days after isch- emia. Field potentials evoked by stimulation of the Schaffer collaterals showed no differences (p > 0.01) from those taken from controls. Postischemic intracellular re- cordings from the CA1 pyramidal cells showed that fast and slow inhibitory postsynaptic potentials were readily evoked on orthodromic stimulation. Together with our previous morphological results, demonstrating survival of hippocampal interneurons following ischemia, we conclude that hippocampal GABAergic interneurons preserve their inhibitory potential in the period preceding delayed CA1 pyramidal cell death. This conclusion taken together with the observation that postischemic 3H-Ro-15-1788 binding in hippocampus declined, sug- gest that benzodiazepines (by increasing the receptor affinity), GABA analogs, and GABA uptake inhibitors may be usefull in the treatment of ischemic CA1 pyra- midal cell death in the rat. Key words: Ischemia - GABA - Autoradiography - Microdialysis - In vitro electrophysiology Rat Offprint requests to: F.F. Johansen (address see above) Introduction The excitatory transmitter, glutamate, is released in ex- citotoxic amounts in the hippocampus CA1 area during cerebral ischemia (Benveniste et al. 1984; Hagberg et al. 1985). Four days later the CA1 pyramidal cells de- generate. The balance between inhibition and excitation is important for normophysiological cell activity, and a disturbance in this balance may result in neuronal death (Saji and Reis 1987). Since agents interfering with the 7-amino-butyric-acid (GABA) receptor-complex protect in part the gerbil CA1 pyramidal cells from ischemic damage (Hallmayer et al. 1985; Kirino et al. 1986; Sternau et al. 1989), it is possible that deficits in hippocampal inhibi- tion precede delayed CA1 pyramidal cell loss in the rat. In a search for morphological evidence of hippocam- pal disinhibition following cerebral ischemia in the rat, our results showed that hippocampal GABAergic neu- rons survived the ischemia (Johansen et al. 1983, 1989a). In this connection, the changes in hippocampal inhibi- tion, demonstrated in the CA3 kainate-lesioned epileptic hippocampus, may be of relevance to the mechanisms in ischemic cell damage. Franck et al. (1988) demonstrated CA1 hyperexcitability associated with loss of both fast and slow inhibitory postsynaptic potentials (IPSPs) in the hippocampal slice preparation (normophysiological ionic enviroment) taken from these animals. Concomi- tantly there was an increased benzodiazepine binding (increased Bmaxand unchanged kd) in CA1. On the other hand, they found no decrease in number of GABAergic somata or terminals, corresponding to our observations in hippocampus after ischemia (Johansen et al. 1989a). They concluded that disinhibition was associated with a disconnection between inhibitory and excitatory ele- ments in CA1. We have, with reference to the observations by Franck et al. (1988), investigated three aspects of the hippocampal GABA system at 1 hour and up to 21 days following cerebral ischemia in the adult rat. These are 1)