Locus coeruleus and neuronal plasticity in a model of focal limbic epilepsy.
OBJECTIVE
A lesion of the noradrenergic nucleus Locus Coeruleus (LC) converts sporadic seizures evoked by microinfusion of bicuculline into the anterior piriform cortex (APC) of rats into limbic status epilepticus (SE). The purpose of this study was to evaluate the chronic effects of this new model of SE on the onset of secondary epileptogenesis. We further related the loss of noradrenaline (NE) with hippocampal mossy fiber sprouting.


METHODS
Male Sprague Dawley rats were treated with systemic saline or DSP-4 (a neurotoxin selective for noradrenergic terminals originating from the LC), microinfused with bicuculline into the APC three days later, and sacrificed after 45 days. Naïve and DSP-4 pretreated sham-operated rats served as respective controls. The following evaluations were performed: (a) monitoring of acute seizures and delayed occurrence of spontaneous recurrent seizures (SRS); (b) NE levels in the hippocampus, frontal and olfactory cortex; (c) occurrence of mossy fiber sprouting into the inner molecular layer of the dentate gyrus of the dorsal hippocampus.


RESULTS
In 30% of rats lacking noradrenergic terminals, SE evoked from the APC was followed by SRS. Conversely, seizures evoked in intact rats did not result in chronic epileptogenesis. Seizures/SE did not modify NE levels as compared with baseline levels both in naïve and DSP-4-pretreated rats. Rats undergoing SE following DSP-4 + bicuculline developed SRS which were accompanied by hippocampal mossy fiber sprouting.


CONCLUSIONS
Noradrenergic loss converts focally induced sporadic seizures into an epileptogenic SE, which is accompanied by mossy fiber sprouting within the dentate gyrus.
Giorgi
Filippo S
FS
Department of Neurosciences, Section of Neurology, University of Pisa, Pisa, Italy.
Mauceli
Giuseppe
G
Blandini
Fabio
F
Ruggieri
Stefano
S
Paparelli
Antonio
A
Murri
Luigi
L
Fornai
Francesco
F
D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000737:chemistry / Q000187:drug effects / Q000503:physiopathology; D004195:Disease Models, Animal; D004828:Epilepsies, Partial / Q000139:chemically induced* / Q000503:physiopathology; D008032:Limbic System / Q000503:physiopathology*; D008125:Locus Coeruleus / Q000737:chemistry / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D019599:Mossy Fibers, Hippocampal / Q000187:drug effects / Q000503:physiopathology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009498:Neurotoxins / Q000494:pharmacology; D009638:Norepinephrine / Q000032:analysis / Q000502:physiology; D009833:Olfactory Pathways / Q000187:drug effects* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride / Q000494:pharmacology; D013226:Status Epilepticus / Q000139:chemically induced* / Q000503:physiopathology
D001596:Benzylamines; D009498:Neurotoxins; D012965:Sodium Chloride; C012102:DSP 4; D009638:Norepinephrine; D001640:Bicuculline