Distance-dependent gradient in NMDAR-driven spine calcium signals along tapering dendrites

Abstract

Neurons receive a multitude of synaptic inputs along their dendritic arbor, but how this highly heterogeneous population of synaptic compartments is spatially organized remains unclear. By measuring -methyl-d-aspartic acid receptor (NMDAR)-driven calcium responses in single spines, we provide a spatial map of synaptic calcium signals along dendritic arbors of hippocampal neurons and relate this to measures of synapse structure. We find that quantal NMDAR calcium signals increase in amplitude as they approach a thinning dendritic tip end. Based on a compartmental model of spine calcium dynamics, we propose that this biased distribution in calcium signals is governed by a gradual, distance-dependent decline in spine size, which we visualized using serial block-face scanning electron microscopy. Our data describe a cell-autonomous feature of principal neurons, where tapering dendrites show an inverse distribution of spine size and NMDAR-driven calcium signals along dendritic trees, with important implications for synaptic plasticity rules and spine function.

Properties of individual hippocampal synapses influencing NMDA-receptor activation by spontaneous neurotransmission

“…This was somewhat surprising given the prevailing notion that GluN2B- NMDARs are not present at synapses after early development (Chen et al, 2000; Barth and Malenka, 2001; Ritter et al, 2002; Yashiro and Philpot, 2008). However, this is consistent with other reports (Sinnen et al, 2016; Walker et al, 2017) and a large and growing amount of evidence suggests that GluN2B-NMDARs are found at mature hippocampal synapses (Kellermayer et al, 2018) and they contribute significantly to synaptic events (Gray et al, 2011; Xiao et al, 2016; Levy et al, 2018). Thus, while it is clear that in some brain areas a developmental switch in NMDAR subtype is pronounced, in the hippocampus it is not as prominent.…”

“…Mean mSCaT amplitude per spine was significantly correlated with distance from the soma (R 2 =0.014, p=0.036 n=316/9) (Fig. 4C), as expected (Walker et al, 2017). Interestingly, even though branch depth was correlated with distance from the soma (R 2 =0.022, p<0.0001; data not shown), branch depth did not correlate with mean mSCaT amplitude (raw data: R 2 = 0.0007, p=0.649, n=287/9) (Fig.…”

“…In the present study, we used an all-optical approach to characterize NMDAR activation following AP-independent (spontaneous) vesicle exocytosis at individual synapses of cultured hippocampal neurons. While GCaMP6f has frequently been used to measure mSCaTs (Andreae and Burrone, 2015; Sinnen et al, 2016; Tang et al, 2016; Walker et al, 2017), we clarified that it offers a large dynamic range and permits detailed analysis of the magnitude of receptor activation. Using this approach, we found that at nearly all synapses in this preparation, GluN2B-NMDARs are the major NMDAR subtype activated during spontaneous synaptic transmission.…”

“…In another series of experiments, we asked whether synapse distance from the soma or degree of branch complexity plays a role in variability in the amount of NMDAR activation. Previous work has suggested that NMDAR-mediated Ca 2+ influx is larger at synapses further away from the soma (Walker et al, 2017). Our data was consistent with this finding and revealed a significant correlation of mSCaT amplitude with the distance of the synapse from the soma, but not with branch complexity.…”

“…Our data was consistent with this finding and revealed a significant correlation of mSCaT amplitude with the distance of the synapse from the soma, but not with branch complexity. However, there is evidence that spine size is correlated with distance from the soma and that more distal synapses tend to be smaller than those more proximal (Katz et al, 2009; Walker et al, 2017). Therefore, the relationship between spine distance and event amplitude may in part arise simply from a larger proportional Ca 2+ influx at a subset of distal spines that are much smaller than proximal spines.…”