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Human Molecular Genetics Advance Access originally published online on January 18, 2009
Human Molecular Genetics 2009 18(6):1075-1088; doi:10.1093/hmg/ddp004
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Expression of mutant β2 nicotinic receptors during development is crucial for epileptogenesis

Irene Manfredi1, Alessia D. Zani2, Luca Rampoldi1,3, Simona Pegorini2, Ilenia Bernascone1,3, Milena Moretti4, Cecilia Gotti4, Laura Croci1, G. Giacomo Consalez1, Luigi Ferini-Strambi5, Mariaelvina Sala2, Linda Pattini6 and Giorgio Casari1,7,8,*

1 San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy 2 Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milan, Via Vanvitelli 32, 20129 Milan, Italy 3 Dulbecco Telethon Institute, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy 4 CNR Institute of Neuroscience, Cellular and Molecular Pharmacology, Department of Medical Pharmacology, University of Milan, Via Vanvitelli 32, 20129 Milan, Italy 5 Sleep Disorders Center, Department of Neurology, San Raffaele Scientific Institute, Via Stamira d'Ancona 20, 20127 Milan, Italy 6 Department of Bioengineering, Politecnico di Milano, P.za Leonardo da Vinci 32, 20133 Milan, Italy 7 Vita-Salute University, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy 8 Istituto Nazionale di Neuroscienze (INN), Via Olgettina 58, 20132 Milan, Italy

* To whom correspondence should be addressed at: Vita-Salute San Raffaele University and Human Molecular Genetics Unit, San Raffaele Scientific Institute, DIBIT, Via Olgettina 58, 20132 Milan, Italy. Tel: +39 0226433502; Fax: +39 0226434767; Email: casari.giorgio{at}hsr.it

Received November 7, 2008; Accepted December 28, 2008

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a focal form of epilepsy characterized by seizures occurring during non-REM sleep. We have developed and characterized the first mouse model for ADNFLE type III carrying the V287L mutation of the β2 subunit of neuronal nicotinic receptor. Mice expressing mutant receptors show a spontaneous epileptic phenotype by electroencephalography with very frequent interictal spikes and seizures. Expression of the mutant β2 subunit is driven by a neuronal-specific tetracycline-controlled promoter, which allows planned silencing of transgene expression in a reversible fashion and tracking the involvement of mutant receptor in crucial phases of epileptogenesis. We found that restricted silencing during development is sufficient to prevent the occurrence of epileptic seizures in adulthood. Our data indicate that mutant nicotinic receptors are responsible for abnormal formation of neuronal circuits and/or long-lasting alteration of network assembly in the developing brain, thus leading to epilepsy.


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