Systemic overexpression of the alpha 1B-adrenergic receptor in mice: an animal model of epilepsy.
OBJECTIVE
A lack of selective alpha1-adrenergic receptor (alpha1-ARs) agonists and antagonists has made it difficult to clarify the precise function of these receptors in the CNS. We recently generated transgenic mice that overexpress either wild-type or a constitutively active mutant alpha 1B-AR in tissues that normally express the receptor. Both wild-type and mutant mice showed an age-progressive neurodegeneration with locomotor impairment and probable stress-induced motor events, which can be partially reversed by alpha 1-AR antagonists. We hypothesized that the wild-type and mutant mice may exhibit spontaneous epileptogenicity as compared with normal (nontransgenic) mice.


METHODS
Normal, wild-type, and mutant mice were studied. Twenty mice (1 year old) underwent prolonged video-EEG monitoring over a 4-week period. Raw EEG data were blindly analyzed by visual inspection for the presence of interictal and ictal epileptic activities.


RESULTS
During the acute postoperative period (< or = 3 days), both wild-type (26.1 +/- 8.07 spikes/day) and mutant mice (116.87 +/- 55.13) exhibited more frequent interictal spikes than did normal mice (2.17 +/- 0.75; p value, <0.05), but all three groups showed EEG and clinical seizures. During the later monitoring periods (>3 days), wild-type and mutant mice showed more frequent interictal spikes (15.44 +/- 4.07; p < 0.01; and 6.05 +/- 2.46; p < 0.05, respectively) as compared with normal mice (0.41 +/- 0.41), but only mutant mice had spontaneous clinical seizures (means +/- SEM).


CONCLUSIONS
The selective overexpression of the alpha 1B-AR is associated with increased in vivo spontaneous interictal epileptogenicity and EEG/behavioral seizures. These results suggest a possible role (direct or indirect) for the alpha 1B-ARs in the development and expression of epileptogenicity.
Kunieda
Takeharu
T
Departments of Neurology and Molecular Cardiology, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Zuscik
Michael J
MJ
Boongird
Atthaporn
A
Perez
Dianne M
DM
Lüders
Hans O
HO
Najm
Imad M
IM
D000818:Animals; D004569:Electroencephalography; D004827:Epilepsy / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics / Q000378:metabolism*; D014743:Videotape Recording
C547717:Adra1b protein, mouse; D018340:Receptors, Adrenergic, alpha-1