| The formation of certain types of long-term memory (LTM) relies on the dynamic nature of neuronal connections in the hippocampus. These long-term modifications that affect synaptic interactions arise from changes in gene transcription and translation that occur as a result of stimuli that induce memory formation. Genetic and pharmacological analyses in animal model systems continue to unravel the molecular mechanisms underlying synaptic plasticity in the hippocampus. The studies presented herein examine two regulatory aspects of the 3′,5′-cyclic adenosine mono-phosphate (cAMP) signal transduction pathway in neuronal processes such as hippocampus-dependent LTM and long-term potentiation (LTP). Behavioral and electrophysiological studies of animals deficient in both Ca++/CaM-stimulated adenylyl cyclase isoforms, AC1 and AC8, reveal the obligatory nature of Ca++ -induced cAMP production in hippocampus-dependent LTM as well as the transcription dependent CA1 LTP and mossy fiber/CA3 LTP. Also shown is the equally important function of the inhibitory protein, Giα1, in hippocampal neuronal plasticity. Mice deficient in Giα1 have elevated hippocampal AC activity and enhanced CA1 LTP. However, the loss of Giα1, through gene ablation, pertussis toxin inactivation, or antisense oligonucleotide-mediated depletion, results in hippocampus-dependent LTM deficits in spite of the apparent enhancements in synaptic efficacy observed in vitro. These results illustrate the importance of stimulatory and inhibitory signaling mechanisms in the process of synaptic plasticity. |
