Competition between recently potentiated synaptic inputs reveals a winner-take-all phase of synaptic tagging and capture

Abstract

Canonical models suggest that mechanisms of long-term memory consist of a synapse-specific, protein synthesis-independent induction phase (changes in synaptic weights/temporary tagging of such synapses) and, within adjacent dendritic compartments, a protein synthesis-dependent distribution phase that may accompany or immediately precede induction and whose protein products enable consolidation through synaptic capture. We now report that this distribution phase is competitive in a "winner-take-all" fashion when synapses potentiated at induction compete with each other for plasticity-related proteins. This finding highlights the importance of synaptic competition in creating stable long-lasting memory in neural networks without disruption.A ctivity-dependent increases and decreases in synaptic efficacy, such as the physiological phenomena of long-term potentiation (LTP) and long-term depression, are considered to be prominent cellular mechanisms mediating learning and memory. Long-lasting persistence of synaptic strength requires protein synthesis that is achieved through transcription and translation (late LTP; L-LTP), whereas short-lasting changes do not involve protein synthesis (early LTP; E-LTP) (1). Based on this dependency on protein synthesis, a sequential model of memory has long been proposed involving the transition from E-LTP to L-LTP, and it remains an important framework for memory consolidation (2, 3). However, the newer concept of synaptic tagging and capture (STC) has changed our understanding of the necessity for a sequential framework. Instead, although memory encoding and tagging occur in real time in association with the event or stimulus to be remembered, the persistence of this trace depends also upon the capture of plasticity-related proteins (PRPs) whose synthesis can be triggered before, during, or immediately after memory encoding. The synthesis of PRPs, now thought to occur in relatively clustered dendritic domains (4, 5), creates the possibility for both synergistic (6) and competitive interactions between potential memories during the subsequent distribution phase. Synergistic effects are well-studied. However, although synaptic competition has been considered previously (7), the temporal dynamics of such competition are not well-understood. We now show that when the temporal persistence of synaptic potentiation is enabled on one pathway by virtue of the availability of PRPs from another earlier or later event, potentiation of a third pathway around the same time may trigger sufficient competition to prevent persistent potentiation on all pathways. Varying the timing of the potentiation of this third pathway enabled one or more pathways to persist whereas others do not. Thus, when the number of competing potential memories increases and the availability of PRPs is limited, a "winner-take-all" scenario appears to prevail whereby some traces persist in a stable manner whereas others do not. The use of multiple pathways models the likely situation in real life when the encoding of multi...

Extinction learning, which consists of the inhibition of retrieval, can be learned without retrieval

“…The posttraining protein synthesis processes take place in different cell regions (the mTOR apparatus and the ribosomes), so it might be necessary to postulate that they may relate to each other by mechanisms linked to the synapses whose plastic changes mediate extinction (30) and the hitherto undescribed synaptic events involved in reconsolidation (20). Such trafficking processes between synapses and protein synthesis systems in hippocampal pyramidal cells have been described by Frey and Morris (33,34), and since then by others (35)(36)(37)(38)(39)(40), as part of the process of synaptic tagging and capture believed to play a key role in the maintenance and interaction of memories (33)(34)(35)(36)(37)(38)(39)(40).…”

Fear Memory

“…Frey and Morris (179,180) and their collaborators (15,16,178,427,525,561,562,638) proposed a cellular mechanism by which relatively weak "early" LTP or LTD in hippocampal synapses lasting only a few minutes may "tag" these synapses with proteins synthesized ad hoc, allowing other proteins produced at other sets of synapses by local LTP or LTD processes (46, 178, 539, 561) to be captured by the tagged synapses, a process that would lead them to strengthen their own LTP or LTD so that their "late phase" (i.e., the one that develops after 3 or 4 h) will last for a long time, lasting hours or days (178 -180). These proteins are called plasticity-related proteins (PRPs) (178,561,638), and their synthesis at synapses depends on the immediate previous involvement of those synapses with LTP and LTD, not on circumstances like arousal.…”

Facilitation of fear extinction by novelty depends on dopamine acting on D1-subtype dopamine receptors in hippocampus

“…This influence is explainable by interactions between new proteins, called plasticity-related proteins (PRPs), at the two sets of synapses; the PRPs that tag one of them can be captured by those of others and enhance their responsiveness (3)(4)(5). Many memories rely on hippocampal LTP and LTD (1,2,(6)(7)(8)(9)(10)(11), and the "synaptic tagging-and-capture" process has been applied to the explanation of interactions between concurrent memories (11)(12)(13), among which are novelty and fear acquisition (12,14) and novelty and fear extinction (15,16).…”