PROFOUND DISTURBANCES OF PRE- AND POST-SYNAPTIC GABA B RECEPTOR-MEDIATED PROCESSES IN REGION CA1 IN A CHRONIC MODEL OF TEMPORAL LOBE EPILEPSY. Mangan, Patrick S., and Eric W. Lothman. Dept. Neurology, University of Virginia Health Sciences Center, Charlottesville, VA. 22908.
APStracts 3:0058N, 1996.
SUMMARY AND CONCLUSIONS
1. This report examines alterations in presynaptic and postsynaptic processes mediated by _-aminobutyric acid-B (GABA B ) receptors within hippocampal region CA1 in a model of chronic temporal lobe epilepsy (TLE). Intracellular recordings were obtained in pyramidal cells from combined hippocampal/parahippocampal control slices and slices obtained > 1 mo after a period of self-sustaining limbic status epilepticus (SSLSE) induced by continuous hippocampal stimulation (CHS). 2. Monosynaptic inhibitory postsynaptic potentials (IPSPs) were evoked by placement of the stimulating electrode in stratum pyramidale within 500 [mu]m of the recording electrode in the presence of ionotropic glutamate receptor antagonists 6-cyano-7- nitroquinoxaline-2,3-dione (CNQX) and D(-)-2-amino-5-phosphonovaleric acid (APV). Control IPSPs exhibited early (GABA A receptor-mediated) and late (GABA B receptor-mediated) components. In contrast, post-SSLSE IPSPs displayed only a GABA A receptor-mediated IPSP. Post-SSLSE IPSPs were completely eliminated by antagonists of the GABA A receptor (bicuculline methiodide and picrotoxin). In control tissue, GABA B receptor antagonists (CGP 55845A, CGP 35348 and 2- hydroxysaclofen) eliminated the late component of the biphasic IPSP but had no discernible effect on IPSPs evoked in post-SSLSE CA1 pyramidal cells. 3. A paired pulse paradigm was employed to investigate the integrity of presynaptic GABA B receptor-mediated inhibition of GABA release. To isolate pure GABA A receptor-mediated responses, and thus facilitate comparison with post-SSLSE tissue, control neurons were penetrated with intracellular electrodes containing Cs 2 SO 4 /QX-314 and IPSPs evoked employing the monosynaptic IPSP protocol. In controls, paired pulses (interpulse intervals (IPIs) of 70-1500 ms) resulted in a diminution of the second IPSP A relative to the first; maximum paired pulse depression (PPD) occurred at an IPI of 100 ms. GABA B receptor antagonists reduced PPD without affecting the amplitude of IPSP A s; the GABA B receptor baclofen reduced the amplitude of both the first and second IPSP A and largely alleviated PPD . In contrast, no PPD was evident at any IPI in post-SSLSE neurons. Neither antagonists nor agonists of GABA B receptor-mediated processes had an effect on either the degree of PPD or the amplitude of IPSPs 4. To better approximate the pattern of CA1 pyramidal cell activation occurring during epileptiform activity, IPSP A s were evoked by trains of stimuli. In controls, mean monosynaptic IPSP A amplitude decreased by approximately 60% during a 3 Hz, 5s train with more than half the decline coming between the first and second IPSPs. In post-SSLSE, no significant IPSP A depression resulted from delivery of stimulus trains. Baclofen reduced the amplitude of control IPSP A s evoked during stimulus trains; both agonist and antagonists significantly lessened the degree of IPSP depression. These same agents altered neither IPSP amplitude or the degree of use-dependent IPSP depression produced in post-SSLSE tissue during stimulus trains. 5. We conclude that a dysfunction of both presynaptic and postsynaptic GABA B receptor-mediated processes occurs in hippocampal area CA1 in the post-SSLSE model of TLE. GABA B receptor agonists and antagonists had no effect on post- SSLSE CA1 pyramidal cell synaptic responses while antagonists of the GABA A receptor completely eliminated IPSPs. Repetitive activation produced no use- dependent synaptic depression. The implications of these findings for the epileptogenic potential of post-SSLSE CA1 and the `dormant basket cell' hypothesis discussed.

Received 15 November 1995; accepted in final form 20 February 1996.
APS Manuscript Number J774-5.
Article publication pending J. Neurophysiol.
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 27 March 96