PROFOUND DISTURBANCES OF PRESYNAPTIC AND POSTSYNAPTIC GABA(B)-RECEPTOR-MEDIATED PROCESSES IN REGION CA1 IN A CHRONIC MODEL OF TEMPORAL-LOBEEPILEPSY

1. This report examines alterations in presynaptic and postsynaptic pr ocesses mediated by gamma-aminobutyric acid-B (GABA(B)) receptors with in 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 obtain ed greater than or equal to 1 mo after a period of self-sustaining lim bic status epilepticus (SSLSE) induced by continuous hippocampal stimu lation. 2. Monosynaptic inhibitory postsynaptic potentials (IPSPs) wer e evoked by placement of the stimulating electrode in stratum pyramida le within 500 mu m of the recording electrode in the presence of the i onotropic glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2, 3-dione and D(-)-2-amino-5-phosphonovaleric acid. Control IPSPs exhibi ted early (GABA(A)-receptor-mediated) and late (GABA(B)-receptor-media ted) 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 pic rotoxin). In control tissue, GABAB receptor antagonists P-(3-aminoprop yl)-P-diethoxymethyl-phosphinic acid (CGP 55845A), 3-N[1-(S)-(3,4-dich lorophenyl) thyl]amino-2-(S)-hydroxypropyl-P-benzyl-phosphinic acid (C GP 35348), and 2-hydroxysaclofen eliminated the late component of the biphasic IPSP but had no discernible effect on IPSPs evoked in post-SS LSE CA1 pyramidal cells. 3. A paired pulse paradigm was employed to in vestigate the integrity of presynaptic GABA(B)-receptor-mediated inhib ition of GABA release. To isolate pure GABA(A)-receptor-mediated respo nses, and thus facilitate comparison with post-SSLSE tissue, control n eurons were penetrated with intracellular electrodes containing Cs2SO4 /lidocaine, N-ethyl bromide (QX-314), and IPSPs were evoked employing the monosynaptic IPSP protocol. In controls, paired pulses [interpulse intervals (IPIs) of 70-1,500 ms] resulted in a diminution of the seco nd early, GABA(A)-receptor mediated chloride IPSP (IPSP,) relative to the first; maximum paired pulse depression (PPD) occurred at an IPI of 100 ms. GABA(B) receptor antagonists reduced PPD without affecting th e amplitude of IPSP(A)s; the GABA(B) receptor agonist baclofen reduced the amplitude of both the first and second IPSPA and largely alleviat ed PPD. In contrast, no PPD was evident at any IPI in post-SSLSE neuro ns. Neither antagonists nor agonists of GABAB-receptor-mediated proces ses had an effect on either the degree of PPD or the amplitude of IPSP s. 4. To better approximate the pattern of CA1 pyramidal cell activati on occurring during epileptiform activity, IPSP(A)s were evoked by tra ins of stimuli. In controls, mean monosynaptic IPSPA amplitude decreas ed by similar to 60% during a 3-Hz, 5-s train, with more than half the decline coming between the first and second IPSPs. In post-SSLSE, no significant IPSPA depression resulted from delivery of stimulus trains . Baclofen reduced the amplitude of control IPSP(A)s evoked during sti mulus trains; both agonist and antagonists significantly lessened the degree of IPSP depression. These same agents altered neither IPSP ampl itude nor the degree of use-dependent IPSP depression produced in post -SSLSE tissue during stimulus trains. 5. We conclude that a dysfunctio n of both presynaptic and post synaptic GABA(B)-receptor-mediated proc esses occurs in hippocampal area CA1 in the post-SSLSE model of TLE. G ABA(B) receptor agonists and antagonists had no effect on post-SSLSE C A1 pyramidal cell synaptic responses, whereas antagonists of the GABA( A) receptor completely eliminated IPSPs. Repetitive activation produce d no use-dependent synaptic depression. The implications of these find ings for the epileptogenic potential of post-SSLSE CA1 and the ''dorma nt basket cell'' hypothesis are discussed.