Evidence That Long-Term Potentiation Occurs within Individual Hippocampal Synapses during Learning

Abstract

Stabilization of long-term potentiation (LTP) depends on multiple signaling cascades linked to actin polymerization. We used one of these, involving phosphorylation of the regulatory protein cofilin, as a marker to test whether LTP-related changes occur in hippocampal synapses during unsupervised learning. Well handled rats were allowed to explore a compartmentalized environment for 30 min after an injection of vehicle or the NMDA receptor antagonist (Ϯ)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP). Another group of rats consisted of vehicle-injected, home-cage controls. Vehicle-treated rats that explored the environment had 30% more spines with dense phosphorylated (p) cofilin immunoreactivity in hippocampal field CA1 than did rats in the home-cage group. The increase in pCofilin-positive spines and behavioral evidence for memory of the explored environment were both eliminated by CPP. Coimmunostaining for pCofilin and the postsynaptic density protein 95 (PSD-95) showed that synapses on pCofilin-positive spines were substantially larger than those on neighboring (pCofilin-negative) spines. These results establish that uncommon cellular events associated with LTP, including changes in synapse size, occur in individual spines during learning, and provide a technique for mapping potential engrams.

Extracellular proteolysis by matrix metalloproteinase-9 drives dendritic spine enlargement and long-term potentiation coordinately

“…When MMP activity is eliminated during TBP, both spine enlargement and potentiation are transient. Our results suggest that MMP-9 functions during LTP as a local, instructive extracellular signal that consolidates synaptic structural and functional modifications coordinately, ensuring persistent modifications critical for learning and memory (30,31). After TBP, there is an immediate increase in both spine size and EPSPs.…”

Up-regulating BDNF with an ampakine rescues synaptic plasticity and memory in Huntington's disease knockin mice

“…There is a large amount of literature linking the hippocampus to this type of activity, and unsupervised paradigms provide multiple dimensions across which to detect behavioral differences (24). The distance traveled by 16-week-old CAG140 mice (n ϭ 19) was reduced relative to WT (Ϫ35 Ϯ 6% on test day 1; P Ͻ 0.0001, n ϭ 17, 2-tailed t test; Fig.…”

“…Mice were tested for 60 min over 4 consecutive days in a complex open-field environment, used previously (24), that lacked objects/compartments on day 1. On testing days 2 and 3, an enclosed dark compartment and 2 identical objects were added to the arena; one object was replaced with a novel object on testing day 4 (Fig.…”

Experiential learning in rodents: past experience enables rapid learning and localized encoding in hippocampus

“…This constitutively active protein severs developing actin filaments unless inactivated by phosphorylation, a step that is critical to the production of the cytoskeletal changes required for LTP consolidation (Chen et al 2007;Rex et al 2009). Previous studies showed that unsupervised learning in a simple open field by rats with no prior experience increases the percentage of hippocampal synapses containing relatively high levels of pCofilin within hippocampal field CA1; an NMDA receptor antagonist blocked both the synaptic changes and memory encoding (Fedulov et al 2007). Studies using other synaptic markers of LTP confirmed that simple unsupervised learning elicits the potentiation effect in the hippocampus of naive rats (Chen et al 2010a,b).…”