Suppressed kindling epileptogenesis and perturbed BDNF and TrkB gene regulation in NT-3 mutant mice.
In the kindling model of epilepsy, repeated electrical stimulations lead to progressive and permanent intensification of seizure activity. We find that the development of amygdala kindling is markedly retarded in mice heterozygous for a deletion of the neurotrophin-3 (NT-3) gene (NT-3+/- mice). These mice did not reach the fully kindled state (3rd grade 5 seizure) until after 28 +/- 4 days of stimulation compared to 17 +/- 2 days in the wild-type animals. The deficit in the NT-3+/- mice reflected dampening of the progression from focal to generalized seizures. The number of stimulations required to evoke focal (grade 1 and 2) seizures did not differ between the groups, but the NT-3 mutants spent a considerably longer period of time (13 +/- 3 days) than wild-type mice (2 +/- 1 days) in grade 2 seizures. As assessed by test stimulation 4-12 weeks after the 10th grade 5 seizure, kindling was maintained in the NT-3 mutants. In situ hybridization showed 30% reduction of basal NT-3 mRNA levels and lack of upregulation of TrkC mRNA expression at 2 h after a generalized seizure in dentate granule cells of the NT-3+/- mice, whereas the seizure-evoked increase in brain-derived neurotrophic factor (BDNF) and TrkB mRNA levels was enhanced. These results indicate that endogenous NT-3 levels can influence the rate of epileptogenesis, and suggest a link between NT-3 and BDNF gene regulation in dentate granule cells.
Elmér
E
E
Department of Clinical Neuroscience, Wallenberg Neuroscience Center, University Hospital, Lund, Sweden.
Kokaia
M
M
Ernfors
P
P
Ferencz
I
I
Kokaia
Z
Z
Lindvall
O
O
D000818:Animals; D001345:Autoradiography; D048588:Benzoxazines; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D018891:Dentate Gyrus / Q000033:anatomy & histology / Q000737:chemistry / Q000503:physiopathology; D004827:Epilepsy / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000502:physiology; D006579:Heterozygote; D017403:In Situ Hybridization; D007696:Kindling, Neurologic / Q000235:genetics*; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants; D009414:Nerve Growth Factors / Q000172:deficiency / Q000235:genetics*; D020933:Neurotrophin 3; D010078:Oxazines; D012333:RNA, Messenger / Q000378:metabolism; D020801:Receptor, Ciliary Neurotrophic Factor; D017475:Receptors, Nerve Growth Factor / Q000235:genetics* / Q000378:metabolism; D012640:Seizures / Q000209:etiology / Q000235:genetics
D048588:Benzoxazines; D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D020933:Neurotrophin 3; D010078:Oxazines; D012333:RNA, Messenger; D020801:Receptor, Ciliary Neurotrophic Factor; D017475:Receptors, Nerve Growth Factor; C028911:cresyl violet