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Developmentally expressed Ca(2+)-sensitive adenylyl cyclase activity is disrupted in the brains of type I adenylyl
1Department of Pharmacology, University of Washington School of Medicine, Seattle 98195, USA.
Abstract:
The type I Ca(2+)-sensitive adenylyl cyclase has been implicated in several forms of synaptic plasticity in vertebrates. Mutant mice in which this enzyme was inactivated by targeted mutagenesis show deficient spatial 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, 220-224). Long term potentiation in the CA1 region of the rat hippocampus develops during the first 2 weeks after birth and reaches maximal expression at postnatal day 15 with a gradual decline at later stages of development. Here we report that Ca(2+)-stimulated adenylyl cyclase activity in rat hippocampus, cerebellum, and cortex increases significantly between postnatal days 1-16. This increase appears to be due to enhanced expression of type I adenylyl cyclase rather than type VIII adenylyl cyclase, the other adenylyl cyclase that is directly stimulated by Ca2+ and calmodulin. Type I adenylyl cyclase mRNA in the hippocampus increased 7-fold during this developmental period. The developmental expression of Ca(2+)-stimulated adenylyl cyclase activity in mouse brain was attenuated in mutant mice lacking type I adenylyl cyclase. Changes in 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 vertebrates.
Insights
Type I adenylyl cyclase expression increases during early development, supporting its role in synaptic plasticity and spatial memory. This enzyme is crucial for long-term potentiation in the vertebrate brain.
Area of Science:
- Neuroscience
- Molecular Biology
- Developmental Biology
Background:
- Type I adenylyl cyclase is linked to synaptic plasticity and spatial memory.
- Mutant mice lacking this enzyme exhibit impaired spatial memory and long-term potentiation.
- Long-term potentiation in the hippocampus develops significantly during the first two weeks after birth.
Purpose of the Study:
- To investigate the developmental expression of Ca(2+)-stimulated adenylyl cyclase activity in the rat brain.
- To determine if the increase in activity is due to Type I or Type VIII adenylyl cyclase.
- To correlate the developmental expression of Type I adenylyl cyclase with the development of long-term potentiation.
Main Methods:
- Measured Ca(2+)-stimulated adenylyl cyclase activity in rat hippocampus, cerebellum, and cortex at various postnatal ages.
- Quantified mRNA levels of Type I and Type VIII adenylyl cyclases.
- Examined Ca(2+)-stimulated adenylyl cyclase activity in brain tissue from mutant mice lacking Type I adenylyl cyclase.
Main Results:
- Ca(2+)-stimulated adenylyl cyclase activity significantly increased in rat brain regions between postnatal days 1-16.
- This increase was primarily attributed to enhanced expression of Type I adenylyl cyclase, with a 7-fold rise in hippocampal mRNA.
- Developmental expression of Ca(2+)-stimulated adenylyl cyclase activity was reduced in mice lacking Type I adenylyl cyclase.
Conclusions:
- The developmental increase in Type I adenylyl cyclase expression correlates with the maturation of long-term potentiation.
- These findings support the hypothesis that Type I adenylyl cyclase is essential for neuroplasticity and spatial memory in vertebrates.