Mice homozygous for the L250T mutation in the alpha 7 nicotinic acetylcholine receptor show increased neuronal apoptosis and die within 1 day of birth

The alpha 7 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 substit ution in the channel domain of the chick alpha 7 nAChR increases agonist af finity and decreases the rate of desensitization, creating a "gain of funct ion" model for this receptor. We have generated mice that express the analo gous mutation (L250T) in the alpha 7 nAChR using the techniques of homologo us recombination and here report their characteristics. Mice heterozygous ( +/T) for the L250T mutation are viable, fertile, and anatomically normal co mpared 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 redu ction in alpha 7 nAChR protein levels and show extensive apoptotic cell dea th throughout the somatosensory cortex. Furthermore, alpha 7 L250T nAChRs a re functionally expressed on neurons within the brains of T/T neonatal mice and have properties that are consistent with those observed for the rat al pha 7 L250T and the chick alpha 7 L247T mutant nAChRs expressed in oocytes. These findings indicate that neurons in the developing brain expressing on ly alpha 7 L250T mutant nAChRs are susceptible to abnormal apoptosis, possi bly due. to increased Ca2+ influx.