Synapses tagged, memories kept: synaptic tagging and capture hypothesis in brain health and disease

Abstract

The synaptic tagging and capture (STC) hypothesis lays the framework on the synapse-specific mechanism of protein synthesis-dependent long-term plasticity upon synaptic induction. Activated synapses will display a transient tag that will capture plasticity-related products (PRPs). These two events, tag setting and PRP synthesis, can be teased apart and have been studied extensively-from their electrophysiological and pharmacological properties to the molecular events involved. Consequently, the hypothesis also permits interactions of synaptic populations that encode different memories within the same neuronal population-hence, it gives rise to the associativity of plasticity. In this review, the recent advances and progress since the experimental debut of the STC hypothesis will be shared. This includes the role of neuromodulation in PRP synthesis and tag integrity, behavioural correlates of the hypothesis and modelling in silico. STC, as a more sensitive assay for synaptic health, can also assess neuronal aberrations. We will also expound how synaptic plasticity and associativity are altered in ageing-related decline and pathological conditions such as juvenile stress, cancer, sleep deprivation and Alzheimer's disease. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Keywords: Synaptic Tagging; hippocampus; long-term depression; long-term potentiation; memory; synaptic plasticity; synaptic tagging and capture.

Figure 1.

Timeline depicting key studies in understanding fundamental properties of STC [2,3] and how STC has been used in different ways to inform on synaptic plasticity processes. These include investigations on the plasticity-related product (PRP) synthesis, compartmentalization [4,5] and regions beyond the CA1 [–9]. Key behavioural [10,11] and computational [12,13] findings are also highlighted. ACC, anterior cingulate cortex; LTD, long-term depression; LTP, long-term potentiation.

Figure 2.

Persistence and associativity of plasticity require STC mechanisms. (a) Weak stimulus, that is weak tetanization (WTET), induces tag setting but not activation of signalling pathways towards PRP synthesis. Thus, the tetanized synapse loses its transient tag and does not exhibit long-lasting potentiation. (b) Strong stimulus (STET) is delivered onto a synapse. This will trigger tag setting and PRP synthesis through signalling cascades (green non-continuous line). PRPs are made available in the neuron and are captured by the tag present in the tetanized synapse. As such, the synapse maintains an input-specific long-lasting LTP. (c) Weak and strong stimuli in temporal proximity (WTET of a synapse occurs in temporal proximity of STET of another synapse). STET induction leads to PRP synthesis. These PRPs are then captured by both tags set by the WTET- and STET-activated synapses. Thus, both synapses exhibit long-lasting potentiation. This is a graphical representation of how associativity of synapses is achieved through STC.