Protein synthesis inhibition and memory: formation vs amnesia

Abstract

Studies using protein synthesis inhibitors have provided key support for the prevalent view that memory formation requires the initiation of protein synthesis as a primary element of the molecular biology of memory. However, many other interpretations of the amnesia data have received far less attention. These include: (a) protein synthesis may play a constitutive role in memory formation, providing proteins prior to an experience that can be activated by training; (b) protein synthesis may be needed to replace proteins available prior to learning but 'consumed' by learning; (c) inhibition of protein synthesis impairs the well-being of neurons, leading to an inability to deliver resources needed for memory formation; and (d) inhibition of protein synthesis results in abnormal neural functions that interfere with memory. One of these, abnormal release of neurotransmitters after inhibition of protein synthesis, is detailed here, along with a review of many circumstances in which it appears that protein synthesis at the time of training is not required for the formation of new memories. Evidence of activation of cell signaling molecules and transcription factors is another form of support for a role of training-initiated protein synthesis in memory. However, recent findings suggest that many of these molecules are activated by training and remain activated for days after training, i.e. activated for times well beyond those typically invoked for memory consolidation processes. Reviewing these results, this paper suggests that the long-lasting molecular changes may be the basis of a form of intracellular memory, one responsible for up-regulating the probability that a neuron, once activated in this manner, will engage in future plasticity. This view melds ideas of modulation of memory with those of consolidation of memory.

Figure 1

Effects of intra-amygdala injections of anisomycin (ANI; 62.5 µg/0.5 µl/side) on memory and on c-Fos immunoreactivity. The anisomycin was injected into the amygdala 20 min prior to inhibitory avoidance training. Left. Anisomycin significantly impaired memory as tested 48 hr after training (p>0.05). Right. Anisomycin blocked training-related increases in c-Fos in sections taken just posterior to the injection site. (From Canal et al., 2007.)

Figure 2

Effects of intra-amygdala injections of anisomycin on release of norepinephrine (NE), dopamine (DA), and serotonin (5-HT) at the site of injection. Note that anisomycin resulted in massive release of each of the biogenic amines during the samples (45 min each) taken immediately after injection. (Data from Canal et al., 2007.)

Figure 3

Effects of intra-amygdala injections of anisomycin on release of norepinephrine, dopamine and serotonin in samples collected during the 8 hrs after injection. These figures are based on the data in Figure 2, except that the y-axis is greatly expanded to reveal the extensive decreases in release of norepinephrine and dopamine that were evident even 8 hr after injection. These levels returned to baseline at 48 hrs (not shown). (Data from Canal et al., 2007.)

Figure 4

Attenuation and induction of amnesia with noradrenergic drugs. The top of the figure shows the timelines for these experiments. The β-adrenergic receptor antagonist, propranolol, administered 10 min prior to anisomycin, attenuated the amnesia, apparently blunting the impact of the large increase in release of NE in response to anisomycin injection. Similarly, the β-adrenergic receptor agonist, clenbuterol, administered 110 min after anisomycin and 10 min prior to training, attenuated the amnesia, apparently blunting the impact of the substantial decrease in release of NE evident 2 hr after training. These results suggest that both the increase and decrease in NE release contribute to anisomycin-induced amnesia. Finally, injections 20 min before training of a high dose of NE alone, i.e. without anisomycin, was sufficient to impair later memory. (Data from Canal et al., 2007.)