Mice homozygous for the L250T mutation in the alpha7 nicotinic acetylcholine receptor show increased neuronal apoptosis and die within 1 day of birth.
The alpha7 nicotinic acetylcholine receptor (nAChR) has been implicated in modulating neurotransmitter release and may play a role in the regulation of neuronal growth and differentiation. A threonine for leucine 247 substitution in the channel domain of the chick alpha7 nAChR increases agonist affinity and decreases the rate of desensitization, creating a "gain of function" model for this receptor. We have generated mice that express the analogous mutation (L250T) in the alpha7 nAChR using the techniques of homologous recombination and here report their characteristics. Mice heterozygous (+/T) for the L250T mutation are viable, fertile, and anatomically normal compared with wild-type littermates. In contrast, homozygous (T/T) L250T mice die within 2-24 h of birth. Brains of T/T mouse pups exhibit a marked reduction in alpha7 nAChR protein levels and show extensive apoptotic cell death throughout the somatosensory cortex. Furthermore, alpha7 L250T nAChRs are functionally expressed on neurons within the brains of T/T neonatal mice and have properties that are consistent with those observed for the rat alpha7 L250T and the chick alpha7 L247T mutant nAChRs expressed in oocytes. These findings indicate that neurons in the developing brain expressing only alpha7 L250T mutant nAChRs are susceptible to abnormal apoptosis, possibly due to increased Ca2+ influx.
Orr-Urtreger
A
A
Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA.
Broide
R S
RS
Kasten
M R
MR
Dang
H
H
Dani
J A
JA
Beaudet
A L
AL
Patrick
J W
JW
D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D017209:Apoptosis / Q000235:genetics*; D003643:Death; D004553:Electric Conductivity; D006579:Heterozygote; D006720:Homozygote; D051379:Mice / Q000235:genetics* / Q000502:physiology; D009154:Mutation / Q000502:physiology*; D009420:Nervous System / Q000033:anatomy & histology; D009474:Neurons / Q000502:physiology*; D009865:Oocytes / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D013003:Somatosensory Cortex / Q000166:cytology / Q000502:physiology; D014982:Xenopus laevis
D011978:Receptors, Nicotinic