Spine Dynamics: Are They All the Same?

Abstract

Since Cajal's first drawings of Golgi stained neurons, generations of researchers have been fascinated by the small protrusions, termed spines, studding many neuronal dendrites. Most excitatory synapses in the mammalian CNS are located on dendritic spines, making spines convenient proxies for excitatory synaptic presence. When in vivo imaging revealed that dendritic spines are dynamic structures, their addition and elimination were interpreted as excitatory synapse gain and loss, respectively. Spine imaging has since become a popular assay for excitatory circuit remodeling. In this review, we re-evaluate the validity of using spine dynamics as a straightforward reflection of circuit rewiring. Recent studies tracking both spines and synaptic markers in vivo reveal that 20% of spines lack PSD-95 and are short lived. Although they account for most spine dynamics, their remodeling is unlikely to impact long-term network structure. We discuss distinct roles that spine dynamics can play in circuit remodeling depending on synaptic content.

Keywords: PSD95; dendritic spines; excitatory synapses; in vivo spine imaging; structural remodeling; synapse formation.

Figure 1. Spines exist on a continuum of morphologies and functions from nonfunctional filopodia like structures to large mature spines

(A) Diagram showing continuum of spine shapes. These spines can be grouped into 3 separate categories, filopodia like structures, immature spines, and mature spines. Distinguishing between these categories based on morphology is extremely difficult due to the limited resolution of light microscopy. (B) The history of a spine can distinguish between these types. (C) In adults, the majority of spines contain a mature synaptic contact, while 20% are either immature or filopodia like. (D) The three categories of spines are difficult to distinguish based on any one category alone. However, by comparing across several criteria the differences become clearer. Reference Key: (1) Zuo, Y. et al. 2005; (2) Dunaevsky, A. et al. 1999; (3) Trachtenberg, J. T. et al. 2002; (4) Holtmaat, A. J. et al. 2005; (5) Villa, K. L. et al. 2016; (6) Cane, M. et al. 2014; (7) Majewska, A. & Sur, M. 2003; (8) Grutzendler, J. et al. 2002; (9) Fiala, J. C. et al. 1998; (10) Knott, G. W. et al. 2006; (11) Arellano, J. I. et al. 2007; (12) Lohmann, C. et al. 2005; (13) Zito, K. et al. 2009; (14) Lambert, J. T. et al. 2017; (15) Ehrlich, I. et al. 2007.

Figure 2. Dynamic spines fall into either the transient or persistent dynamics categories

(A) Example of two persistent dynamic events where a new spine forms and persists long term. (B) Example of two transient dynamic events which appear and disappear again with a few days. (C and D) Examples of spine dynamics. Left, middle, and right panels show three-channel merge, Teal-gephyrin alone, and PSD-95-mCherry alone, respectively. Arrows denote dynamic spines: filled when spine is present and empty when spine is absent. (C) Shows the brief appearance and removal of spines without PSD-95 at separate nearby locations. (D) Shows formation of two new spines that gain a PSD-95 and persist. Adapted from (Villa 2016).

Figure 3. Different strategies commonly used for sampling dendritic spine dynamics

(A). Daily imaging easily distinguishes between transient and persistent dynamic spines (blue circles indicate spine presence). This imaging interval is less than the approximately 1–4 day lifetime of transient spines (Holtmaat 2005), so that the majority of transient and persistent events will be detected in this approach. (B) Imaging twice with a longer interval, ranging from a week to over a month, will allow persistent dynamics to accumulate giving a good indication of long term changes in connectivity. However, shorter, transient events that represent a plasticity related sampling strategy will be missed. (C) Imaging two times at relatively short intervals leads to the converse problem, where the inability to distinguish between transient and persistent spines leads to an overestimation of persistent dynamic spines. (D) The addition of a third imaging session, longer than 4 days, allows the outcome of a dynamic event to be tracked in terms of spine survival and the correct scoring of transient vs persistent events. (E) Imaging sessions that are performed too close together, hours or days apart, cannot be used to infer whether a spine will persist or is only transiently present since these intervals are within the mean lifetime of transient spines. (F) PSD-95 (red) can be used in lieu of an extended dynamic history to differentiate between eliminated spines that do not form mature synaptic contacts and those that do.