Protein synthesis and consolidation of memory-related synaptic changes

Abstract

Published findings and new results described here challenge this idea. Protein synthesis inhibitors did not prevent Theta Bust Stimulation (TBS) from producing extremely stable longterm potentiation (LTP) in experiments using standard hippocampal slice protocols. However, the inhibitors were effective under conditions that likely depleted protein levels prior to attempts to induce the potentiation effect. Experiments showed that induction of LTP at one input, and thus a prior episode of protein synthesis, eliminated the effects of inhibitors on potentiation of a second input even in depleted slices. These observations suggest that a primary role of translation and transcription processes initiated by learning events is to prepare neurons to support future learning. Other work has provided support for an alternative theory of consolidation. Specifically, if the synaptic changes that support memory are to endure, learning events/TBS must engage a complex set of signaling processes that reorganize and re-stabilize the spine actin cytoskeleton. This is accomplished in fast (10 min) and slow (50 min) stages with the first requiring integrin activation and the second a recovery of integrin functioning. These results align with, and provide mechanisms for, the long-held view that memories are established and consolidated over a set of temporally distinct phases.

Linking Memories across Time via Neuronal and Dendritic Overlaps in Model Neurons with Active Dendrites

“…For example, plasticity markers such as pHluorin-tagged glutamate receptors (Zhang et al., 2015) and phosphorylated cofilin (Lynch et al., 2015), as well as two-photon in vivo imaging (Fu et al., 2012, Makino and Malinow, 2011), could be used to test the distributions of potentiated synapses after learning. Evidence for widespread plasticity across a majority of neurons, with localized clusters of potentiated synapses within a small subset of their dendritic branches, would indicate that local (as opposed to somatic) PRP mechanisms predominate during associative memory formation.…”

Synaptic activation of ribosomal protein S6 phosphorylation occurs locally in activated dendritic domains

“…It is possible that their results depended on the fact that the pulselabeling was under conditions of short-term amino acid starvation. Under these conditions, proteins critical for structural remodeling and consolidation may be depleted (Lynch et al 2014). In this regard, it is noteworthy that the consequences of protein synthesis inhibitors also depend on the time of application (Kelleher et al 2004a).…”

Pharmacogenomics of antidepressant drugs: perspectives for the personalization of treatment in depression

“…Previous associations between rs3800373 C / rs1360780 T and antidepressant response were found during the early phase of treatment (2-3 weeks), while the present results contributed in clarifying the role of these SNPs later in treatment and in TRD patients. In TRD hypothalamic-pituitary-adrenal (HPA) axis activity is reset at a higher level, although feedback remains intact (54,55) while increased resistance of the HPA axis to the feedback of corticosteroids was reported in broad MDD (56). These observations suggest that TRD patients may suffer from specific detrimental effects of FKBP5 polymorphisms that reduce the efficiency of the HPA negative feedback.…”

“…Integrins are heterodimeric (one alpha and one beta subunit) transmembrane proteins that connect the extracellular environment to intracellular signaling. In the CNS they are involved in the control of synaptic plasticity, longterm potentiation (LTP), cell adhesion and migration (53,54). Polymorphisms in another beta isoform (ITGB3) and expression level of this gene have been associated with antidepressant response in humans (42,55).…”