anisomycin and Epilepsy

In electrophysiological terms, experimental models of durable information storage in the brain include long-term potentiation (LTP), long-term depression, and kindling. Protein synthesis correlates with these enduring processes. We propose a fourth example of long-lasting information storage in the brain, which we call the GABA-withdrawal syndrome (GWS). In rats, withdrawal of a chronic intracortical infusion of GABA, a ubiquitous inhibitory neurotransmitter, induced epileptogenesis at the infusion site. This overt GWS lasted for days. Anisomycin, a protein synthesis inhibitor, prevented the appearance of GWS in vivo. Hippocampal and neocortical slices showed a similar post-GABA hyperexcitability in vitro and an enhanced susceptibility to LTP induction. One to four months after the epileptic behavior disappeared, systemic administration of a subconvulsant dose of pentylenetetrazol produced the reappearance of paroxysmal activity. The long-lasting effects of tonic GABAA receptor stimulation may be involved in long-term information storage processes at the cortical level, whereas the cessation of GABAA receptor stimulation may be involved in chronic pathological conditions, such as epilepsy. Furthermore, we propose that GWS may represent a common key factor in the addiction to GABAergic agents (for example, barbiturates, benzodiazepines, and ethanol). GWS represents a novel form of neurono-glial plasticity. The mechanisms of this phenomenon remain to be understood.

Topics: Animals; Anisomycin; Cerebral Cortex; Convulsants; Electric Stimulation; Epilepsy; gamma-Aminobutyric Acid; In Vitro Techniques; Injections; Long-Term Potentiation; Male; Pentylenetetrazole; Protein Synthesis Inhibitors; Rats; Rats, Wistar; Substance Withdrawal Syndrome; Time Factors

Picrotoxin (50 microM) elicited rhythmic synchronized bursting in CA3 pyramidal cells in guinea pig hippocampal slices. Addition of the selective group I metabotropic glutamate receptor (mGluR) agonist (S)-3,5-dihydroxyphenylglycine (25 microM) elicited an increase in burst frequency. This was soon followed by a slowly progressive increase in burst duration (BD), converting the brief 250-520 ms picrotoxin-induced synchronized bursts into prolonged discharges of 1-5 s in duration. BD was significantly increased within 60 min and reached a maximum after 2-2.5 h of agonist exposure. The protein synthesis inhibitors anisomycin (15 microM) or cycloheximide (25 microM) significantly impeded the mGluR-mediated development of the prolonged bursts; 90-120 min of agonist application failed to elicit the expected burst prolongation. By contrast, the mGluR-mediated enhancement of burst frequency progressed unimpeded. Furthermore, protein synthesis inhibitors had no significant effect on the frequency or duration of fully developed mGluR-induced prolonged discharges. These results suggest that the group I mGluR-mediated prolongation of synchronized bursts has a protein synthesis-dependent mechanism.

Topics: Action Potentials; Animals; Anisomycin; Brain Chemistry; Convulsants; Epilepsy; Excitatory Amino Acid Antagonists; Glycine; Guinea Pigs; Neurons; Periodicity; Picrotoxin; Protein Synthesis Inhibitors; Receptors, Metabotropic Glutamate; Resorcinols

We have been examining the role of protein synthesis in the development and maintenance of spontaneous bursting in the rat hippocampal slice. We used stimulus train induced bursting (STIB) as an in vitro model for epileptogenesis, to study the effects of 3 different protein synthesis inhibitors (cycloheximide, anisomycin, puromycin) on the development of bursting. We report here that none of these inhibitors blocked the induction of bursting, suggesting that protein synthesis is not essential for the development of electrically induced bursting. However, when established spontaneous bursting was examined in the presence of cycloheximide, the duration of the bursting phase was markedly reduced, suggesting that the maintenance of spontaneous bursting in the early hours requires ongoing protein synthesis.

Topics: Animals; Anisomycin; Cycloheximide; Epilepsy; Hippocampus; In Vitro Techniques; Male; Nerve Tissue Proteins; Neuronal Plasticity; Puromycin; Rats; Rats, Sprague-Dawley