Single Synapse LTP: A Matter of Context?

Abstract

The most commonly studied form of synaptic plasticity is long-term potentiation (LTP). Over the last 15 years, it has been possible to induce structural and functional LTP in dendritic spines using two-photon glutamate uncaging, allowing for studying the signaling mechanisms of LTP with single synapse resolution. In this review, we compare different stimulation methods to induce single synapse LTP and discuss how LTP is expressed. We summarize the underlying signaling mechanisms that have been studied with high spatiotemporal resolution. Finally, we discuss how LTP in a single synapse can be affected by excitatory and inhibitory synapses nearby. We argue that single synapse LTP is highly dependent on context: the choice of induction method, the history of the dendritic spine and the dendritic vicinity crucially affect signaling pathways and expression of single synapse LTP.

Keywords: dendritic spine; glutamate uncaging; long-term potentiation; molecular pathways; synaptic crosstalk; synaptic plasticity.

FIGURE 1

The choice of LTP induction method can affect spine growth. To induce spine growth and functional LTP in single synapses, activation of NMDA receptors (dark blue) is required. Removing the magnesium block (purple) from the NMDA channel pore can be achieved in two ways: (Left) glutamate uncaging (light blue) is performed in the absence of extracellular magnesium (Mg²⁺-free). In this case, tetrodotoxin (TTX) is added to prevent aberrant plasticity due to spontaneous activity. This type of stimulation typically induces rapid, strong initial growth (peak phase), after which the spine volume stabilizes at a lower level (plateau phase). (Right) In paired protocols, two-photon glutamate uncaging (light blue) is paired with depolarization (in voltage clamp by increasing the holding potential, or in current clamp by inducing a backpropagating action potential). Paired stimulation typically leads to a gradual growth of the dendritic spine over time. AMPA receptors in the spine head are depicted in red. The dashed gray lines reflect that the correlation between stimulation protocol and temporal profile of spine growth is not absolute.

FIGURE 2

Interactions between synapses. (A) When LTP is induced in a single spine using glutamate uncaging (blue), this leads to the spread of threshold-lowering signals (purple) in the dendrite. When a nearby spine receives a stimulus that is normally subthreshold, spine growth will occur. Threshold-lowering signals include the small GTPases Ras, Rac1 and RhoA (Harvey et al., 2008; Murakoshi et al., 2011; Hedrick et al., 2016) and BDNF-TrkB signaling (Harward et al., 2016; Colgan et al., 2018). PKA and ERK activity also spreads over the dendrite but it is unclear if these kinases are able to lower the LTP threshold (Zhai et al., 2013). (B) During development, the calcium influx in a single spine during glutamate uncaging can trigger calcium-induced calcium release (yellow). This leads to propagating calcium waves in the dendrite, and a nearby spine receiving a stimulus that is normally subthreshold will now show spine growth (Lee et al., 2016). (C) When a cluster of spines undergo LTP, this can lead to the activation of shrinkage signals. These signals can induce shrinkage of an unstimulated dendritic spine nearby (Oh et al., 2015). (D) When a cluster of spines undergo LTP, this can lead to the production of a retrograde messenger by the postsynaptic neuron. This messenger can trigger the growth of a presynaptic inhibitory bouton (green) nearby (Hu et al., 2019). (E) When vesicle fusion in the presynapse (gray) has been blocked for a prolonged period of time, this can lead to a lowering of the LTP threshold: when a spine receives a stimulus that is normally subthreshold, it will show spine growth (Lee et al., 2010).