| The theory that de novo protein synthesis is necessary for memory consolidation is widely accepted, yet supported by evidence based primarily on results using protein synthesis inhibitors. Injection of a protein synthesis inhibitor near the time of training often spares memory of the training experience for a short time yet impairs memory tested at long intervals after training. These results imply that "short-term memory" is protein synthesis independent, yet establishment of a "long-term memory" trace or memory consolidation processes require protein synthesis. However, there are conflicting data showing that protein synthesis inhibitors can in some cases impair memory tested at both short and long intervals after training. Moreover, a number of studies show that several different pharmacological agents can attenuate the memory impairments caused by protein synthesis inhibitors without affecting the level of protein synthesis inhibition. These results suggest that protein synthesis inhibitors may affect memory processing through mechanisms other than protein synthesis inhibition. We hypothesized that protein synthesis inhibitors impair memory by altering release of the biogenic amines, neurotransmitters important for modulating the strength of memory. We tested this hypothesis using two protein synthesis inhibitors, anisomycin, a non-selective protein synthesis inhibitor, and CREB antisense, which impairs CREB-mediated gene transcription. At doses commonly used in the literature, both drugs reliably impaired memory when infused into the hippocampus and amygdala, yet in a task-dependent manner. Also, as assessed via microdialysis, both drugs impaired the release of norepinephrine, and anisomycin drastically disrupted the release of all the biogenic amines. Furthermore, attempts to pharmacologically block the effects on neurotransmitter release caused by the protein synthesis inhibitors attenuated the memory impairments. Collectively, the data provide strong support for the idea that protein synthesis inhibitors impair memory by disrupting neurotransmitter release important for memory modulation processes. The findings are interpreted to suggest that memory modulation theory better accounts for the effects on memory from administration of protein synthesis inhibitors than memory consolidation theory. |
