DEVELOPMENTALLY EXPRESSED CA2-SENSITIVE ADENYLYL-CYCLASE ACTIVITY IS DISRUPTED IN THE BRAINS OF TYPE-I ADENYLYL-CYCLASE MUTANT MICE()

The type I Ca2+-sensitive adenylyl cyclase has been implicated in seve ral forms of synaptic plasticity in vertebrates. Mutant mice in which this enzyme was inactivated by targeted mutagenesis show deficient spa tial memory and altered long term potentiation (Wu, Z. L., Thomas, S. A., Villacres, E., C., Xia, Z., Simmons, M. L., Chavkin, C., Palmiter, R. D., and Storm, D. R. (1995) Proc. Natl Acad Sci. U.S.A. 92, 220-22 4). Long term potentiation in the CA1 region of the rat hippocampus de velops during the first 2 weeks after birth and reaches maximal expres sion at postnatal day 15 with a gradual decline at later stages of dev elopment. Here we report that Ca2+-stimulated adenylyl cyclase activit y in rat hip pocampus, cerebellum, and cortex increases significantly between postnatal days 1-16. This increase appears to be due to enhanc ed expression of type I adenylyl cyclase rather than type VIII adenyly l cyclase, the other adenylyl cyclase that is directly stimulated by C a2+ and calmodulin. Type I adenylyl cyclase mRNA in the hippocampus in creased 7-fold during this developmental period. The developmental exp ression of Ca2+-stimulated adenylyl cyclase activity in mouse brain wa s attenuated in mutant mice lacking type I adenylyl cyclase. Changes i n expression of the type I adenylyl cyclase during the period of long term potentiation development are consistent with the hypothesis that this enzyme is important for neuroplasticity and spatial memory in ver tebrates.