Homosynaptic and Heterosynaptic Inhibition of Synaptic Tagging and Capture of Long-Term Potentiation by Previous Synaptic Activity

Abstract

Long-term potentiation (LTP) is an enhancement of synaptic strength that may contribute to information storage in the mammalian brain. LTP expression can be regulated by previous synaptic activity, a process known as "metaplasticity." Cell-wide occurrence of metaplasticity may regulate synaptic strength. However, few reports have demonstrated metaplasticity at synapses that are silent during activity at converging synaptic inputs. We describe a novel form of cell-wide metaplasticity in hippocampal area CA1. Low-frequency stimulation (LFS) decreased the stability of long-lasting LTP ["late" LTP (L-LTP)] induced later at the same inputs (homosynaptic inhibition) and at other inputs converging on the same postsynaptic cells (heterosynaptic inhibition). Significantly, heterosynaptic inhibition of L-LTP also occurred across basal and apical dendrites ("heterodendritic" inhibition). Because transient early LTP (E-LTP) was not affected by previous LFS, we examined the effects of LFS on the consolidation of E-LTP to L-LTP. The duration of E-LTP induced at one set of inputs can be extended by capturing L-LTP-associated gene products generated by previous activity at other inputs to

Synapse-specific stabilization of plasticity processes: The synaptic tagging and capture hypothesis revisited 10 years later

“…These critical experiments were later independently replicated by Frey's (Sajikumar and Frey, 2004a) and Morris's (O'Carroll and Morris, 2004) groups, and by other labs working both in the mammalian hippocampus (Young and Nguyen, 2005) and in Aplysia neuronal cultures (Casadio et al, 1999). They arguably represent the strongest evidence supporting the STC model.…”

“…For example, it has been suggested that low frequency stimulation (LFS) can prevent the formation of the synaptic tag, although does not affect L-LTP-associated gene expression (Young and Nguyen, 2005). Depotentiating stimuli have no effect on already captured L-LTP (Barco et al, 2002;Young and Nguyen, 2005), but they do eliminate synaptic tags within 5-10…”

“…Depotentiating stimuli have no effect on already captured L-LTP (Barco et al, 2002;Young and Nguyen, 2005), but they do eliminate synaptic tags within 5-10…”

“…This transient depression somehow prevents the formation of new synaptic tags for a given time window, but does not interfere with the burst of gene expression in the cell nucleus (Young and Nguyen, 2005). The cellular and molecular mechanisms underlying this cell-wide effect of LFS remain undetermined.…”

“…As described in a previous section, capture of L-LTP can occur within both the basilar and the apical dendritic compartment in response to the same tagging signal. However, capture across compartments required a stronger stimulation (Alarcon et al, 2006;Sajikumar et al, 2007b), which could be needed to set a compartmental tag that overcame the structural or molecular constrains that restricted capture across compartments, making the new gene products available in the different dendritic compartments within a neuron (Fonseca et al, 2004;Sajikumar et al, 2007a;Sajikumar et al, 2007b;Young and Nguyen, 2005). The different stimulation thresholds gating the interaction between synaptic inputs during the regimes of cell-wide facilitation, compartment-restricted plasticity and synaptic capture can enable a neuron to differentially integrate information arriving from different brain areas into its distinct functional compartments as a function of the strength of the stimuli and their temporal proximity.…”