Systemic Overexpression of the α1B-Adrenergic Receptor in Mice: An Animal Model of Epilepsy


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Summary:  Purpose: A lack of selective α1-adrenergic receptor (α1-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 α1B-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 α1-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 (≤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 α1B-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 α1B-ARs in the development and expression of epileptogenicity.