Activity-dependent coordination of presynaptic release probability and postsynaptic GluR2 abundance at single synapses

Abstract

The strength of an excitatory synapse depends on both the presynaptic release probability (p r) and the abundance of functional postsynaptic AMPA receptors. How these parameters are related or balanced at a single synapse remains unknown. By taking advantage of live fluorescence imaging in cultured hippocampal neurons where individual synapses are readily resolved, we estimate p r by labeling presynaptic vesicles with a styryl dye, FM1-43, while concurrently measuring postsynaptic AMPA receptor abundance at the same synapse by immunolabeling surface GluR2. We find no appreciable correlation between pr and the level of surface synaptic GluR2 under basal condition, and blocking basal neural activity has no effect on the observed lack of correlation. However, elevating network activity drives their correlation, which accompanies a decrease in mean GluR2 level. These findings provide the direct evidence that the coordination of pre-and postsynaptic parameters of synaptic strength is not intrinsically fixed but that the balance is tuned by synaptic use at individual synapses.hippocampal culture ͉ synaptic strength ͉ FM1-43 ͉ neurotransmitter release ͉ glutamate receptor I n the classical Katz model of synaptic transmission, the weight of each synapse is determined by p r and quantal size (q), as p r ϫ q (1, 2). Because q is largely governed by postsynaptic receptors, synapses have to regulate both pre-and postsynaptic mechanisms to control the overall synaptic strength. Across a population of synapses, p r (3) and postsynaptic receptor level (4) are highly heterogeneous. Therefore, it is of fundamental importance to identify how the relationship between pre-and postsynaptic strengths at individual synapses is organized. For instance, the balance between the two could be compensative, synergistic, or random. Amongst a synapse population, compensative balance would result in relatively uniform synaptic strengths. In contrast, synergistic balance would result in a biased or skewed distribution of synaptic strengths. Thus, the manner in which preand postsynaptic strengths are balanced might influence dendritic processing and operation of neural networks.Previous studies on synaptic structure and physiology suggest for a positive correlation between p r and postsynaptic surface AMPA receptor level. For example, the number of AMPA receptors is correlated to postsynaptic density (PSD) size (5, 6), which, in turn, is matched to the presynaptic active zone length (7). Also, a larger presynaptic active zone supports a larger pool of readily releasable synaptic vesicles, resulting in higher p r (8,9). In further support of the view that p r and postsynaptic surface AMPA receptor abundance are correlated, overexpression of postsynaptic proteins such as PSD-95, Shank, or GluR2 enhances AMPA receptor clustering and increases spine size, and these postsynaptic changes are, in turn, accompanied by enhanced presynaptic release (10-12). Nevertheless, beyond these reports, no studies to date have directly addressed how p r and postsyna...

Independent Vesicle Pools Underlie Different Modes of Release during Neuronal Development

“…Furthermore, the correlation between the size of the activity-dependent pool and PSD-95 staining at individual synapses was significant at 14 DIV but not at 10 DIV. Previous data has shown matching of synaptic strength between presynaptic and postsynaptic compartments, both structurally (Schikorski and Stevens, 1999) and functionally (Tokuoka and Goda, 2008;Kay et al, 2011) in mature neurons. Previous data from our lab has demonstrated that, at 10 DIV, individual synapses show strong correlation at a structural level but no correlation functionally (Kay et al, 2011), begging the question: which side drives functional matching?…”

Stress at Learning Facilitates Memory Formation by Regulating AMPA Receptor Trafficking Through a Glucocorticoid Action

“…Interestingly, a positive correlation between the abundance of postsynaptic GluA2 and presynaptic release probability at single synapses follows enhanced network activity in cultured hippocampal neurons (Tokuoka and Goda, 2008). Synaptic adhesion molecules have been suggested as potential candidates to promote this correlation, given their ability to link the presynaptic and postsynaptic terminals in an activity-dependent manner (Tokuoka and Goda, 2008).…”

“…GluA2 has a critical role in controlling various AMPAR properties, including Ca2 + permeability, subunit assembly of AMPARs (Derkach et al, 2007;Sprengel, 2006), and AMPAR synaptic targeting (Lu et al, 2009). In the hippocampus, the GluA2 subunit mainly occurs in principal pyramidal neurons (Tokuoka and Goda, 2008) and excitatory synaptic currents appear to be primarily mediated by GluA2-containing AMPARs (Plant et al, 2006).…”

Neuronal activity drives matching of pre- and postsynaptic function during synapse maturation

“…Observations at the ultrastructural level suggest that there is indeed a high degree of correlation between bouton volume, total vesicle number, active zone area, postsynaptic density area and spine volume [5][6][7][8]. Whilst concrete experimental evidence in support of a functional correlation is lacking, indirect evidence suggests that presynaptic release probability is not correlated with postsynaptic surface GluR2 levels, unless neurons are grown in a medium conducive to high levels of activity [9].…”