title: Removal of G(ialpha1) constraints on adenylyl cyclase in the hippocampus enhances LTP and impairs memory formation.
abstract: Stimulation of adenylyl cyclase in the hippocampus is critical for memory formation. However, generation of cAMP signals within an optimal range for memory may require a balance between stimulatory and inhibitory mechanisms. The role of adenylyl cyclase inhibitory mechanisms for memory has not been addressed. One of the mechanisms for inhibition of adenylyl cyclase is through activation of G(i)-coupled receptors, a mechanism that could serve as a constraint on memory formation. Here we report that ablation of G(ialpha1) by gene disruption increases hippocampal adenylyl cyclase activity and enhances LTP in area CA1. Furthermore, gene ablation of G(ialpha1) or antisense oligonucleotide-mediated depletion of G(ialpha1) disrupted hippocampus-dependent memory. We conclude that G(ialpha1) provides a critical mechanism for tonic inhibition of adenylyl cyclase activity in the hippocampus. We hypothesize that loss of G(ialpha1) amplifies the responsiveness of CA1 postsynaptic neurons to stimuli that strengthen synaptic efficacy, thereby diminishing synapse-specific plasticity required for new memory formation.
authors.affiliation: Department of Pharmacology, The University of Washington, Seattle, 98195, USA.
authors.forename: Victor V
authors.initials: VV
authors.lastname: Pineda
authors.forename: Jaime I
authors.initials: JI
authors.lastname: Athos
authors.forename: Hongbing
authors.initials: H
authors.lastname: Wang
authors.forename: Jeremy
authors.initials: J
authors.lastname: Celver
authors.forename: Danielle
authors.initials: D
authors.lastname: Ippolito
authors.forename: Guylain
authors.initials: G
authors.lastname: Boulay
authors.forename: Lutz
authors.initials: L
authors.lastname: Birnbaumer
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Storm
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D017353:Gene Deletion; D006624:Hippocampus / Q000201:enzymology* / Q000502:physiology; D017774:Long-Term Potentiation / Q000502:physiology*; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D037342:Pertussis Toxin / Q000494:pharmacology
chemical_list: D037342:Pertussis Toxin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D000262:Adenylyl Cyclases