Activity Dependent and Independent Determinants of Synaptic Size Diversity

Abstract

The extraordinary diversity of excitatory synapse sizes is commonly attributed to activity-dependent processes that drive synaptic growth and diminution. Recent studies also point to activity-independent size fluctuations, possibly driven by innate synaptic molecule dynamics, as important generators of size diversity. To examine the contributions of activity-dependent and independent processes to excitatory synapse size diversity, we studied glutamatergic synapse size dynamics and diversification in cultured rat cortical neurons (both sexes), silenced from plating. We found that in networks with no history of activity whatsoever, synaptic size diversity was no less extensive than that observed in spontaneously active networks. Synapses in silenced networks were larger, size distributions were broader, yet these were rightward-skewed and similar in shape when scaled by mean synaptic size. Silencing reduced the magnitude of size fluctuations and weakened constraints on size distributions, yet these were sufficient to explain synaptic size diversity in silenced networks. Model-based exploration followed by experimental testing indicated that silencing-associated changes in innate molecular dynamics and fluctuation characteristics might negatively impact synaptic persistence, resulting in reduced synaptic numbers. This, in turn, would increase synaptic molecule availability, promote synaptic enlargement, and ultimately alter fluctuation characteristics. These findings suggest that activity-independent size fluctuations are sufficient to fully diversify glutamatergic synaptic sizes, with activity-dependent processes primarily setting the scale rather than the shape of size distributions. Moreover, they point to reciprocal relationships between synaptic size fluctuations, size distributions, and synaptic numbers mediated by the innate dynamics of synaptic molecules as they move in, out, and between synapses.

Stable but not rigid: Long-termin vivoSTED nanoscopy uncovers extensive remodeling of stable spines and indicates multiple drivers of structural plasticity

“…Furthermore, head sizes varied more strongly not only at any given time point but also their changes over time were more variable compared to WT mice. The head size increase we observed could well represent homeostatic scaling to counteract for the loss of synaptic input 46 as a recent study demonstrated an increase in synaptic size and a broader distribution of the same in silenced neuronal networks 22 . The enhanced dynamics of spine head sizes in SOD tg mice moreover argue for a higher level of synaptic remodelling, hence synaptic instability.…”

“…The dynamics of spine synapses, however, is only partially driven by neuronal impulse activity and synaptic transmission 10,22 . Learning-associated changes typically seem immersed in a background of spontaneous ongoing change.…”

Estimation of the number of synapses in the hippocampus and brain-wide by volume electron microscopy and genetic labeling

“…This trait has also been described in the rat neocortex 28,29 . This type of distribution is characterized by a skewed curve with a long tail to the right, and it has been found in other synaptic parameters such as synaptic strength, spike transmission probability, and the size of unitary excitatory postsynaptic potentials [30][31][32][33] . It is thus tempting to suggest that the size of the synaptic junction is correlated with these and other functional characteristics of the synapse, as has been proposed previously 29 .…”

Three-dimensional synaptic organization of the human hippocampal CA1 field

“…Although the extraordinary diversity of excitatory synapse sizes is commonly attributed to activity-dependent processes that drive synaptic growth and diminution, recent studies also point to activity-independent size fluctuations, possibly driven by innate synaptic molecule dynamics, as important generators of size diversity. Specifically, activity-dependent processes seem to primarily dictate the scale rather than the shape of synaptic size distributions ( Hazan and Ziv, 2020 ).…”