Abstract | PURPOSE:
gamma-Aminobutyric acid receptor ( GABA(A)r) subunit beta3-deficient mice model Angelman syndrome by displaying impaired learning, abnormal EEG with interictal spikes and slowing, myoclonus, and convulsions. The beta3-subunit deficiency causes a failure of intrathalamic reticular nucleus inhibition, leading to abnormally synchronized thalamocortical oscillations. We postulated that this pathophysiology underlies the abnormal cortical EEG and triggers interictal spikes and seizures, but extrathalamic regions also contribute to interictal spikes and seizures, so that the EEG slowing should reveal an absence-like response profile, whereas spikes and seizures have dual responsiveness to absence and partial-seizure drugs. METHODS: Recording electrodes were implanted over the parietal cortices of wild-type, heterozygotes, and homozygous null mice. In each experiment, EEG was recorded for 45 min, either drug or vehicle administered, and EEG recorded for another 3 h. Each EEG was scored for slow-wave activity, interictal spikes, and seizures by a reader blinded to treatments. RESULTS: CONCLUSIONS: The results suggest that this model of Angelman syndrome, although not expressing typical absence seizures, is characterized by hypersynchronous thalamocortical oscillations that possess absence-like pharmacologic responsiveness and promote EEG slowing, interictal spikes, and convulsive seizures.
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Authors | Adrian Handforth, Timothy M Delorey, Gregg E Homanics, Richard W Olsen |
Journal | Epilepsia
(Epilepsia)
Vol. 46
Issue 12
Pg. 1860-70
(Dec 2005)
ISSN: 0013-9580 [Print] United States |
PMID | 16393151
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
- Anticonvulsants
- GABA Agonists
- GABA Antagonists
- Organophosphorus Compounds
- Receptors, GABA-A
- Ethosuximide
- CGP 35348
- Baclofen
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Topics |
- Angelman Syndrome
(drug therapy, metabolism, physiopathology)
- Animals
- Anticonvulsants
(pharmacology, therapeutic use)
- Baclofen
(pharmacology)
- Cerebral Cortex
(drug effects, physiopathology)
- Disease Models, Animal
- Electrodes, Implanted
- Electroencephalography
(drug effects, statistics & numerical data)
- Ethosuximide
(pharmacology)
- Female
- GABA Agonists
(pharmacology)
- GABA Antagonists
(pharmacology)
- Humans
- Male
- Mice
- Mice, Mutant Strains
- Neural Pathways
(physiopathology)
- Organophosphorus Compounds
(pharmacology)
- Parietal Lobe
(physiopathology)
- Receptors, GABA-A
(deficiency, drug effects, physiology)
- Thalamus
(drug effects, physiopathology)
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