Neuron
Volume 41, Issue 1, 8 January 2004, Pages 153-163
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Article
Removal of Giα1 Constraints on Adenylyl Cyclase in the Hippocampus Enhances LTP and Impairs Memory Formation

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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 Gi-coupled receptors, a mechanism that could serve as a constraint on memory formation. Here we report that ablation of Giα1 by gene disruption increases hippocampal adenylyl cyclase activity and enhances LTP in area CA1. Furthermore, gene ablation of Giα1 or antisense oligonucleotide-mediated depletion of Giα1 disrupted hippocampus-dependent memory. We conclude that Giα1 provides a critical mechanism for tonic inhibition of adenylyl cyclase activity in the hippocampus. We hypothesize that loss of Giα1 amplifies the responsiveness of CA1 postsynaptic neurons to stimuli that strengthen synaptic efficacy, thereby diminishing synapse-specific plasticity required for new memory formation.

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