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'
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