Profound disturbances of pre- and postsynaptic GABA(B)-receptor-mediated processes in region CA1 in a chronic model of temporal lobe epilepsy

1. This report examines alterations in presynaptic and postsynaptic processes mediated by gamma-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 greater than or equal to 1 mo after a period of self-sustaining limbic status epilepticus (SSLSE) induced by continuous hippocampal stimulation. 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 the ionotropic glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione and D(-)-2-amino-5-phosphonovaleric acid. 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, GABAB receptor antagonists P-(3-aminopropyl)-P-diethoxymethyl-phosphinic acid (CGP 55845A), 3-N[1-(S)-(3,4-dichlorophenyl) ethyl]amino-2-(S)-hydroxypropyl-P-benzyl-phosphinic acid (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 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 second 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 the amplitude of IPSP(A)s; the GABA(B) receptor agonist baclofen reduced the amplitude of both the first and second IPSPA and largely alleviated PPD. In contrast, no PPD was evident at any IPI in post-SSLSE neurons. Neither antagonists nor agonists of GABAB-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 IPSPA amplitude decreased 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 stimulus trains; both agonist and antagonists significantly lessened the degree of IPSP depression. These same agents altered neither IPSP amplitude nor 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 post synaptic 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, whereas 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 are discussed.