The interplay between neuronal activity and actin dynamics mimic the setting of an LTD synaptic tag

Abstract

Persistent forms of plasticity, such as long-term depression (LTD), are dependent on the interplay between activity-dependent synaptic tags and the capture of plasticity-related proteins. We propose that the synaptic tag represents a structural alteration that turns synapses permissive to change. We found that modulation of actin dynamics has different roles in the induction and maintenance of LTD. Inhibition of either actin depolymerisation or polymerization blocks LTD induction whereas only the inhibition of actin depolymerisation blocks LTD maintenance. Interestingly, we found that actin depolymerisation and CaMKII activation are involved in LTD synaptic-tagging and capture. Moreover, inhibition of actin polymerisation mimics the setting of a synaptic tag, in an activity-dependent manner, allowing the expression of LTD in non-stimulated synapses. Suspending synaptic activation also restricts the time window of synaptic capture, which can be restored by inhibiting actin polymerization. Our results support our hypothesis that modulation of the actin cytoskeleton provides an input-specific signal for synaptic protein capture.

Actin remodeling, the synaptic tag and the maintenance of synaptic plasticity

“…This suggests that a transient remodeling of actin is necessary for the capture of PRPs at activated synapses. [72][73][74] As shown previously, in our experimental setting, inhibiting the activation of CaMKII also blocks the setting of the synaptic tag, irrespectively of whether LTP or LTD was induced. 70,72,73 Interestingly, inhibiting actin polymerization rescued the effect of inhibiting CaMKII, showing that actin dynamics is downstream of CaMKII activation.…”

“…[72][73][74] As shown previously, in our experimental setting, inhibiting the activation of CaMKII also blocks the setting of the synaptic tag, irrespectively of whether LTP or LTD was induced. 70,72,73 Interestingly, inhibiting actin polymerization rescued the effect of inhibiting CaMKII, showing that actin dynamics is downstream of CaMKII activation. In LTD, we also showed that inhibiting actin polymerization is sufficient to create an artificial synaptic tag that can capture PRPs and express a maintained form of LTD by a tagging and capture mechanism.…”

“…We have recently shown that pharmacological modulation of actin dynamics, bi-directionally interferes with LTP and LTD maintenance, by tagging and capture mechanisms. 72,73 We found that inhibiting actin polymerization or depolymerization at the time of induction, interferes with LTP and LTD maintenance, suggesting that actin dynamics is necessary for both LTP and LTD. This was also demonstrated in a previous study by Ramachandran et al, which use actin polymerization inhibitors to show that LTP induction is dependent on a dynamic actin.…”

“…This was also demonstrated in a previous study by Ramachandran et al, which use actin polymerization inhibitors to show that LTP induction is dependent on a dynamic actin. 74 Interestingly, the effect of blocking actin dynamics during maintenance has opposite effects in LTP or LTD. 72,73 In the case of LTP, inhibiting actin polymerization blocks its maintenance, while blocking actin depolymerization has no effect; in LTD this is the opposite.…”

Temporal gating of synaptic competition in the lateral amygdala by cannabinoid receptor modulation of the thalamic input

“…In this working model, synaptic cooperation and competition are determined by a balance between PRPs availability (source) and the strength of the tag (sink). In turn, the tag strength is a combination of the number of activated synapses and the ability that each synapse has in capturing PRPs (Fonseca, 2012;Szabó et al, 2016). Previous studies looking at competition in CA1 hippocampal synapses have shown that competition was correlated with the strength of the tag (Fonseca et al, 2004).…”