Beyond boundaries: extended temporal flexibility in synaptic tagging and capture

Abstract

Synaptic tagging and capture (STC) is a mechanism that enables the formation of associative synaptic plasticity by marking activated synapses with "tags" to capture plasticity-related products (PRPs) essential for plasticity stabilization. Experimental evidence using long-term potentiation (LTP), a widely studied cellular correlate of memory, shows that the duration of synaptic tags varies, lasting up to 90 minutes in ex vivo hippocampal slices but shorter in in vivo conditions, likely due to higher metabolic activity. In this study, we investigate the time window for tag-PRP interactions in STC using a strong-before-weak paradigm, where protein synthesis-dependent late-LTP precedes protein synthesis-independent early-LTP at various intervals. Surprisingly, successful STC is observed even with a 9-hour interval in the strong-before-weak paradigm, suggesting a broader temporal flexibility for tag-PRP interactions than previously understood. This unexpected finding offers alternative explanations for associative memory formation by cataloguing memory events, allowing weaker memories to be strengthened when preceded by stronger ones.

Fig. 1. Extended associativity in strong-before-weak synaptic tagging and capture paradigm.

a Schematic representation of a transverse hippocampal slice showing the location of electrodes in the CA1 region. Recording electrode (rec) positioned onto CA1 apical dendrites was flanked by two stimulating electrodes, S1 and S2, placed in the stratum radiatum (sr) layer to stimulate two independent Schaffer collateral (sc) synaptic inputs of the same neuronal population. b A weak tetanization (WTET, single train of 21 pulses at 100 Hz) applied to S2 (blue circle) induced a significant potentiation that gradually decayed to baseline level (n = 7 slices from 5 animals). The control input S1 (red circles) remained stable throughout the recording period. Strong-before-weak STC paradigm where a strong tetanization (STET, 3 trains of 100 pulses at 100 Hz, inter-trains interval of 10 min) was applied to S1 (red circles) followed by a WTET applied to S2 (blue circles) at various intervals, (c) 0.5 h (n = 8 slices from 5 animals), (d) 3 h (n = 7 slices from 6 animals), (e) 6 h (n = 7 slices from 7 animals), (f) 9 h (n = 7 slices from 5 animals). The LTPs induced in S1 and S2 maintained at potentiated level throughout the recording period in all cases. Analogue traces show typical fEPSP of S1 (red) and S2 (blue) at 15 min of baseline (dotted line), 10 min after LTP induction (dashed line), and at the end of the recording (solid line). Scale bar for all traces: 3 mV/5 ms. Three red arrows represent STET, whereas single blue arrow represents WTET. All data are represented as mean ± SEM.

Fig. 2. Extended interval in weak-before-strong synaptic tagging and capture paradigm fails to show associativity.

a WTET applied to S2 (blue circles) followed by a STET applied to S1 (red circles) at a 0.5 h interval showed associativity where both LTPs sustained at potentiated level throughout the recording period (n = 7 slices from 5 animals). b When the interval between WTET and STET increased to 3 h, the WTET induced an early-form of LTP that gradually decayed to baseline level (n = 7 slices from 5 animals). Analogue traces show typical fEPSP of S1 (red) and S2 (blue) at 15 min of baseline (dotted line), 10 min after LTP induction (dashed line), and at the end of the recording (solid line). Scale bar for all traces: 3 mV/5 ms. Three red arrows represent STET, whereas a single blue arrow represents WTET. All data are represented as mean ± SEM.

Fig. 3. Strong tetanization lowers LTP induction threshold in neighbouring synapses.

a A weak tetanus protocol (short-term potentiation (STP), 14 pulses at 100 Hz) applied to S2 (blue circles) induced a transient potentiation that returned to baseline level within 30 min (n = 10 slices from 5 animals). b STP (14 pulses) applied to S2 (blue circles) followed by STET applied to S1 (red circles) at a 1 h interval did not affect the STP-induced potentiation (n = 8 slices from 4 animals). c When STET was induced in S1 (red circles) followed by STP (14 pulses) in S2 (blue circles), the STP induced a long-lasting potentiation that sustained throughout the recording period (n = 7 slices from 3 animals). d Similar experiment as in c, except that the STP was replaced with an even weaker tetanus (11 pulses at 100 Hz). The STP-induced potentiation did not transform into a long-term potentiation in this case (n = 8 slices from 3 animals). Analogue traces show typical fEPSP of S1 (red) and S2 (blue) at 15 min of baseline (dotted line), 10 min after LTP induction (dashed line), and at the end of the recording (solid line). Scale bar for all traces: 3 mV/5 ms. Three red arrows represent STET, whereas single blue arrow represents STP (11 or 14 pulses). All data are represented as mean ± SEM.

Fig. 4. An illustration of the effective time window for synaptic/behavioural tagging and capture under behavioural tagging and ex vivo conditions.

The arrow at 0 h time point indicates the timing where the strong TET/training is induced. Under ex vivo condition, no associativity is observed when weak TET precedes strong TET by 3 h. Associativity is observed for up to at least 9 h following strong TET induction. The effective associativity window is shorter under behavioural tagging conditions (dotted grey line). TET: tetanization.