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.

Intrahippocampal infusions of anisomycin produce amnesia: Contribution of increased release of norepinephrine, dopamine, and acetylcholine

“…The results obtained with propranolol pretreatment add to extensive evidence that a host of pharmacological agents can rescue memory from the effects of protein synthesis inhibitors (cf. Barraco and Stettner 1976;Martinez et al 1981;Davis and Squire 1984;Routtenberg and Rekart 2005;Gold 2006Gold , 2008. Substantial increases in the release of dopamine and acetylcholine were also seen after anisomycin treatment.…”

“…However, other consequences of protein synthesis inhibition may also be important for causing amnesia, including abnormal neurophysiological activity (Agnihotri et al 2004;Xu et al 2005), gene superinduction, and apoptosis (cf. Routtenberg and Rekart 2005;Gold 2008;Radulovic and Tronson 2008;Routtenberg 2008;Rudy 2008). …”

“…The present findings do not challenge the extensive evidence of changes in gene and protein expression patterns after training (cf. Clayton 2000; Levenson and Sweatt 2005;Abraham and Williams 2008;Gold 2008;Klann and Sweatt 2008). These changes are likely to participate in cellular responses important for brain functions including neural memory and plasticity, although the relationship to specific behavioral memories is less clear.…”

“…Despite the centrality of experience-induced protein synthesis in contemporary models of memory formation, the necessity of protein synthesis for memory consolidation and long-term potentiation (LTP) stabilization has been questioned since the beginning of experiments of this type (e.g., Flexner and Goodman 1975;Barraco and Stettner 1976;Flood et al 1978;Martinez et al 1981), and continues to be questioned in several recent reviews (Routtenberg and Rekart 2005;Gold 2006Gold , 2008Radulovic and Tronson 2008;Routtenberg 2008;Rudy 2008). There are many instances of intact memories formed in the presence of extensive inhibition of protein synthesis, and a wide range of behavioral and pharmacological manipulations can rescue memory impaired by protein synthesis inhibitors.…”

Synaptic and extrasynaptic traces of long-term memory: the ID molecule theory

“…A separate line of inquiry, also directed at the participation of molecules in learning and memory, has linked performance in behavioral tasks to the application of protein synthesis inhibitors (see Davis and Squire, 1984;Nader et al, 2000;Gold, 2008). In an extension of the same effort, a long list of small polypeptide molecules, the neuropeptides, has been compiled and sequenced over the past years (see Fricker, 2012;Borbély et al, 2013).…”