Paroxysmal inhibitory potentials mediated by GABAB receptors in partially disinhibited rat hippocampal slice cultures.

Abstract

SUMMARY1. Intracellular recording techniques were used to study synaptic potentials in CA3 pyramidal cells elicited with mossy fibre stimulation in partially disinhibited hippocampal slice cultures. Two experimental protocols were used: (1) high concentrations (20-40 gM) of the A-type y-aminobutyric acid (GABAA) receptor antagonist bicuculline plus low concentrations (2-4 /sM) of the glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), or (2) low concentrations (1-2 5 ,lM) of bicuculline alone.2. Under the first condition, stimulation of mossy fibre afferents evoked epileptic bursts alternating with a response consisting of an excitatory postsynaptic potential (EPSP) followed by an unusually large and long-lasting hyperpolarizing potential with a maximal amplitude in the range of -30 mV from the resting membrane potential.3. This paroxysmal inhibitory potential (PIP) had a reversal potential near that of potassium. The amplitude of the PIP was not dependent on action potentials superimposed on the preceding EPSP, and was present in cells recorded with microelectrodes containing the Ca2" chelator EGTA. These data suggest that the PIP is not a Ca2"-activated K+ potential.4. The PIP was prolonged by the GABA-uptake blocker nipecotic acid, was reduced by hyperpolarizing interneurons with the opioid agonist FK 33-824, and was abolished by the GABAB-receptor antagonist CGP 35 348. These data indicate that the PIP is mediated by the activation of GABAB receptors following GABA release from interneurons.5. The NMDA-receptor antagonist D-2-amino-5-phosphonovalerate (D-APV) strongly reduced the amplitude of the PIP, but had no effect on the GABAB receptor-mediated inhibitory postsynaptic potential (IPSP) under control conditions.6. Under the first condition, regular stimulation elicited a cyclical pattern of evoked responses. There was either an alternation between an epileptic burst and a PIP or, at shorter interstimulus intervals, a sequence of gradually increasing PIPs followed by an epileptic burst, which then reset the cycle. Under the second condition, in low concentrations of bicuculline alone, the early GABAA-mediated IPSP was little affected, but the late GABAB-mediated IPSP was greatly enhanced. These enhanced late IPSPs were comparable in amplitude and duration to the PIPs seen under the first conditions, could exhibit cyclical behaviour, and were reduced by D-APV.8. Application of CGP 35 348 abolished the late IPSP under control conditions, but had no effect on hippocampal excitability. In contrast, CGP 35 348 blocked the PIP elicited in low bicuculline, and consequently led to intense epileptic discharge.9. We suggest that the amplification of GABAB receptor-mediated synaptic potentials after partial disinhibition may be an important endogenous compensatory mechanism preventing epileptogenesis.

Low-Probability Transmission of Neocortical and Entorhinal Impulses Through the Perirhinal Cortex

“…Although synaptic inhibition is ubiquitous in the cerebral cortex, our findings suggest that it plays a particularly important role in the perirhinal cortex. As was reported in other cortical regions (Dutar and Nicoll 1988;McCormick 1989;Scanziani et al 1991), principal perirhinal neurons display GABA A and GABA B responses (Biella et al 2001;Garden et al 2002;Martina et al 2001).…”

Epileptiform Synchronization and GABAB Receptor Antagonism in the Juvenile Rat Hippocampus

“…Previous in vitro work has shown that antagonizing GABA B receptor is not sufficient per se to cause epileptiform synchronization (McCormick, 1989;Sutor and Luhmann, 1998), but it can potentiate epileptiform responses induced by GABA A receptor antagonists (McCormick, 1989;Scanziani et al, 1991Scanziani et al, , 1994Karlsson et al, 1992;Sutor and Luhmann, 1998). Overall, these data suggested that weakening or abolishing GABA A receptor-mediated inhibition should be a sine qua non condition for expressing the proepileptogenic effects of CGP 35348.…”

“…Hence, our data indicate that the capacity of GABA B receptor-mediated mechanisms to modulate epileptiform synchronization in cortical networks maintained in vitro does not depend on GABA A receptor antagonism but rather on the ability of ambient GABA to activate type B receptors located pre-and postsynaptically. This condition can be achieved by increasing neuronal excitability, and thus GABA release, either by blocking the GABA A receptor function (McCormick, 1989;Scanziani et al, 1991Scanziani et al, , 1994Sutor and Luhmann, 1998) or by applying drugs capable of augmenting transmitter release (e.g., 4AP). (1 mM) on the activity generated in the CA3 area during application of 4AP and excitatory amino acid receptor antagonists.…”

“…The contribution of GABA B receptor-mediated mechanisms to seizure generation remains unclear. For instance, GABA B receptor antagonists can prolong epileptiform discharges in cortical networks (McCormick, 1989;Scanziani et al, 1991Scanziani et al, , 1994Sutor and Luhmann, 1998), but in other studies, GABA B receptor activation exerts proconvulsant effects. This has been documented both in clinical practice (Rush and Gibberd, 1990;Kofler et al, 1994) and in experimental models Watts and Jefferys, 1993;Motalli et al, 1999).…”

γ-Aminobutyric Acid Type B Receptors with Specific Heterodimer Composition and Postsynaptic Actions in Hippocampal Neurons Are Targets of Anticonvulsant Gabapentin Action

“…Fast postsynaptic GABA A responses result from activity at single synapses, whereas slower GABA B responses necessitate the synchronous activation of multiple presynaptic fibers (Otis and Mody, 1992). In addition, postsynaptic GABA B receptors seem important for curtailing epileptiform activity in the presence of impaired GABA A inhibition (Malouf et al, 1990;Scanziani et al, 1991). In hippocampal neurons, postsynaptic GABA B receptor activation leads to membrane hyperpolarization, mediated by inwardly rectifying potassium channels (Luscher et al, 1997).…”