Impaired cerebellar long-term potentiation in type I adenylyl cyclase mutant mice.
Activation of adenylyl cyclase and the consequent production of cAMP is a process that has been shown to be central to invertebrate model systems of information storage. In the vertebrate brain, it has been suggested that a presynaptic cascade involving Ca influx, cAMP production, and subsequent activation of cAMP-dependent protein kinase is necessary for induction of long-term potentiation (LTP) at the cerebellar parallel fiber-Purkinje cell synapse. We have used mutant mice in which the major Ca-sensitive adenylyl cyclase isoform of cerebellar cortex (type I) is deleted to show that this results in an approximately 65% reduction in cerebellar Ca-sensitive cyclase activity and a nearly complete blockade of cerebellar LTP assessed using granule cell-Purkinje cell pairs in culture. This blockade is not accompanied by alterations in a number of basal electrophysiological parameters and may be bypassed by application of an exogenous cAMP analog, suggesting that it results specifically from deletion of the type I adenylyl cyclase.
Storm
D R
DR
Department of Pharmacology, University of Washington, Seattle 98195, USA.
Hansel
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C
Hacker
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Parent
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Linden
D J
DJ
D000262:Adenylyl Cyclases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000201:enzymology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005684:Gait / Q000502:physiology; D018698:Glutamic Acid / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000502:physiology; D009412:Nerve Fibers / Q000201:enzymology; D011597:Psychomotor Performance / Q000502:physiology; D011689:Purkinje Cells / Q000166:cytology / Q000201:enzymology* / Q000648:ultrastructure; D013873:Thionucleotides / Q000494:pharmacology
D004791:Enzyme Inhibitors; D013873:Thionucleotides; D018698:Glutamic Acid; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D000242:Cyclic AMP; D000262:Adenylyl Cyclases