Increased ethanol resistance and consumption in Eps8 knockout mice correlates with altered actin dynamics.
Dynamic modulation of the actin cytoskeleton is critical for synaptic plasticity, abnormalities of which are thought to contribute to mental illness and addiction. Here we report that mice lacking Eps8, a regulator of actin dynamics, are resistant to some acute intoxicating effects of ethanol and show increased ethanol consumption. In the brain, the N-methyl-D-aspartate (NMDA) receptor is a major target of ethanol. We show that Eps8 is localized to postsynaptic structures and is part of the NMDA receptor complex. Moreover, in Eps8 null mice, NMDA receptor currents and their sensitivity to inhibition by ethanol are abnormal. In addition, Eps8 null neurons are resistant to the actin-remodeling activities of NMDA and ethanol. We propose that proper regulation of the actin cytoskeleton is a key determinant of cellular and behavioral responses to ethanol.
Offenhäuser
Nina
N
Fondazione Istituto FIRC di Oncologia Molecolare, Via Adamello 16, 20139 Milan, Italy. nina.offenhauser@ifom-ieo-campus.it
Castelletti
Daniela
D
Mapelli
Lisa
L
Soppo
Blanche Ekalle
BE
Regondi
Maria Cristina
MC
Rossi
Paola
P
D'Angelo
Egidio
E
Frassoni
Carolina
C
Amadeo
Alida
A
Tocchetti
Arianna
A
Pozzi
Benedetta
B
Disanza
Andrea
A
Guarnieri
Douglas
D
Betsholtz
Christer
C
Scita
Giorgio
G
Heberlein
Ulrike
U
Di Fiore
Pier Paolo
PP
D000199:Actins / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000428:Alcohol Drinking; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D002531:Cerebellum / Q000166:cytology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism*; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D002492:Central Nervous System Depressants; D003598:Cytoskeletal Proteins; C083430:Eps8 protein, mouse; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D000431:Ethanol