Abstracts

RATIONALE: Progress toward elucidating the function of alpha1B-adrenergic receptors (alpha1BARs) in the central nervous system has been constrained by a lack of agonists and antagonists with adequate alpha1B- specificity. We recently generated transgenic mice that overexpress the alpha1BARs in tissues that normally express the receptor, including the brain. Some of the transgenic mice showed locomotor impairment and probable seizures that can be partially reversed by the alpha1AR antagonist terazosin. We hypothesized that the transgenic or wild type may exhibit spontaneous epileptogenicity as compared to normal (non transgenic mice).
METHODS: Twenty mice (one year old) were anesthetized with sodium pentobarbital (60mg/kg, intraperitoneal: Nembutal), and implanted using epidural electrodes in the frontal and parietal lobes bilaterally. Prolonged video-EEG monitoring was performed using the digital video-EEG monitoring (Vangard). Experiments were carried out over four weeks period on each mouse. EEG data analyses were performed using a bipolar montage. Whole EEG samples were blindly analyzed by visual inspection for the presence of interictal and ictal activities. At the end of monitoring, the mice were sacrificed for histological and immunocytochemistry studies.
RESULTS: During the acute post-operative period ([lte] 3 days), wild type exhibited more frequent interictal spikes ( 26.1[plusminus]8.07 spikes/hr) than normal mice ( 2.17[plusminus]0.75 ) (p-value [lt] 0.05). Three types of mice showed EEG & clinical seizures. During the later monitoring period ([gt] 3 days), both the transgenic type and wild type mice demonstrated more frequent interictal spikes ( 15.44[plusminus]4.07 , p[lt]0.01; 6.05[plusminus]2.46 , p [lt]0.05, respectively ) as compared to normal mice ( 0.41[plusminus]0.41 ). Only the transgenic mice showed EEG & clinical seizures during the later monitoring periods. Immunocytochemical staining revealed an increased expression of the NMDA receptor 2B subunit (NRB) in the neocortex and hippocampal formation as compared to normal and wild type mice.
CONCLUSIONS: The selective hyperexpression of the adrenergic alpha-1 receptor is associated with increased interictal epileptogenicity and EEG/behavioral seizures. The results suggest the possibility of a role (direct or indirect) of the alpha-1-adrenergic receptor. Further studies on the mechanisms of the development of epileptogenicity in these mice overexposing these receptors remain unknown.