Limbic network interactions leading to hyperexcitability in a model of temporal lobe epilepsy.
In mouse brain slices that contain reciprocally connected hippocampus and entorhinal cortex (EC) networks, CA3 outputs control the EC propensity to generate experimentally induced ictal-like discharges resembling electrographic seizures. Neuronal damage in limbic areas, such as CA3 and dentate hilus, occurs in patients with temporal lobe epilepsy and in animal models (e.g., pilocarpine- or kainate-treated rodents) mimicking this epileptic disorder. Hence, hippocampal damage in epileptic mice may lead to decreased CA3 output function that in turn would allow EC networks to generate ictal-like events. Here we tested this hypothesis and found that CA3-driven interictal discharges induced by 4-aminopyridine (4AP, 50 microM) in hippocampus-EC slices from mice injected with pilocarpine 13-22 days earlier have a lower frequency than in age-matched control slices. Moreover, EC-driven ictal-like discharges in pilocarpine-treated slices occur throughout the experiment (< or = 6 h) and spread to the CA1/subicular area via the temporoammonic path; in contrast, they disappear in control slices within 2 h of 4AP application and propagate via the trisynaptic hippocampal circuit. Thus, different network interactions within the hippocampus-EC loop characterize control and pilocarpine-treated slices maintained in vitro. We propose that these functional changes, which are presumably caused by seizure-induced cell damage, lead to seizures in vivo. This process is facilitated by a decreased control of EC excitability by hippocampal outputs and possibly sustained by the reverberant activity between EC and CA1/subiculum networks that are excited via the temporoammonic path.
D'Antuono
Margherita
M
Montreal Neurological Institute and Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 2B4, Canada.
Benini
Ruba
R
Biagini
Giuseppe
G
D'Arcangelo
Giovanna
G
Barbarosie
Michaela
M
Tancredi
Virginia
V
Avoli
Massimo
M
D015761:4-Aminopyridine; D000818:Animals; D004195:Disease Models, Animal; D018728:Entorhinal Cortex / Q000187:drug effects / Q000503:physiopathology; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced / Q000503:physiopathology*; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D066298:In Vitro Techniques; D008032:Limbic System / Q000187:drug effects / Q000503:physiopathology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018721:Muscarinic Agonists / Q000494:pharmacology; D009415:Nerve Net / Q000187:drug effects / Q000503:physiopathology*; D019580:Perforant Pathway / Q000187:drug effects / Q000503:physiopathology; D010862:Pilocarpine / Q000494:pharmacology; D026902:Potassium Channel Blockers
D018721:Muscarinic Agonists; D026902:Potassium Channel Blockers; D010862:Pilocarpine; D015761:4-Aminopyridine