Ethosuximide Improves the EEG in Model of Angelman Syndrome
Abstract number :
1.013
Submission category :
Year :
2000
Submission ID :
2342
Source :
www.aesnet.org
Presentation date :
12/2/2000 12:00:00 AM
Published date :
Dec 1, 2000, 06:00 AM
Authors :
Adrian Handforth, Anton Asatourian, Geetanjali Sharma, Timothy M Delorey, Pradeep K Banerjee, Richard W Olsen, Gregg E Homanics, VA-GLAHS, Los Angeles, CA; UCLA, Los Angeles, CA; U Pittsburgh, Pittsburg, PA.
RATIONALE:_We previously reported that mice lacking the beta-3 subunit of the GABA receptor display many features of human Angelman syndrome, a common cause of mental retardation and epilepsy in children, including impaired learning, disturbed sleep/wake cycles, abnormal electrocortical rhythms, and spontaneous seizures (J Neurosci 18:8505, 1998). In this quantitative EEG study, we investigated whether ethosuximide improves electrocortical activity. METHODS:_Adult GABA receptor beta-3 subunit knockout (-/-), heterozygote (+/-), and littermate controls (+/+) were studied. Two epidural screws over parietal cortex permitted EEG recordings. Animals had a baseline 45-minute recording (Grass Model 8), then received drug or vehicle, 10 ml/kg i.p., and recording continued for another 2.5 hours. The experiment was repeated at least 1 day later with the opposite treatment. Drugs used were ethosuximide 400 mg/kg, carbamazepine 20 mg/kg and 60 mg/kg. A reader blinded to treatments visually quantified the percentage of the EEG record that displayed abnormal background rhythms, and the frequency of interictal epileptiform spikes. RESULTS:_During the 2.5-hour post-treatment recording, -/- and +/- mice displayed abnormal EEG for 25-40% of the time when given saline. Ethosuximide suppressed abnormal electrocortical activity to near-zero values (p<0.001). Interictal spiking averaged 6/min in +/- and 15/min in -/- mice with saline treatment, whereas ethosuximide virtually abolished interictal spiking (p<0.01, p<0.001, respectively). In contrast, carbamazepine, 20 mg/kg or 60 mg/kg, had no significant effect on abnormal EEG or interictal spiking. CONCLUSIONS:_Ethosuximide, a selective low-threshold calcium channel blocker, exhibited a normalizing effect on electrocortical activity and suppressed interictal spiking in heterozygote and homozygote GABA receptor beta-3 deficient mice. This finding supports the notion that thalamocortical physiology is abnormal in these mice, suggests that ethosuximide may be beneficial for Angelman syndrome.