, 2007). Furthermore, diffusion within the synapse may display a complex behavior

swapping from one microdomain to another. This behavior needs to be aligned with the inhomogeneous distribution of scaffolding proteins (Fukata et al., 2013, MacGillavry et al., 2013, Nair et al., 2013 and Specht et al., 2013), thus defining subdomains within the PSD. Notably, the diffusion and the trapping of the receptor can be regulated by the activity of the neuron via phosphorylation events that tune the scaffold-scaffold (e.g., Charrier et al., Dinaciclib price 2010) or the receptor-scaffold (e.g., Opazo et al., 2010, Mukherjee et al., 2011 and Specht et al., 2011) interactions. The demonstration that the molecular dynamics of receptor-scaffold interactions can be regulated physiologically (Triller and Choquet, 2008) has reinforced

the notion that molecular movements can link physiology and morphology by providing access to the chemistry in the living cell. The measurement of dwell times and the knowledge of the number of copies of each molecular species together with the three-dimensional organization of the molecules will give access to a real chemistry in living cells, a chemistry “in cellulo.” In fact, the dwell time within a multimolecular assembly reflects association and dissociation constants. Furthermore, high-density single-molecule imaging and statistical approaches provided access to the energies involved in the trapping of receptors at synapses (Hoze et al., 2012, Masson et al., 2009 and Türkcan et al., BMS-777607 mw 2012). The diffusion

trapping of receptors and the dynamics of scaffolding proteins, each with specific physical constraints and properties, is at the origin of time-dependent fluctuations in molecule numbers referred to as a “molecular noise.” It reflects the rate of entry and exit of molecules from the PSD. Fluctuations in the number of receptors, which is one of the determinants of the amplitude of the postsynaptic potential (PSP), may account for part of the variability in PSP amplitudes observed between repeated identical patterns of stimulation (Heine et al., 2008a). However, other stochastic found processes such as vesicular release, transmitter diffusion, or channel kinetics also contribute to time-dependent PSP variability (Ribrault et al., 2011b). Thus, receptor-associated molecular noise is an important parameter not only in setting the robustness of the synaptic response, but also in accounting for the stochastic molecular interactions among the constituents of the PSD. This molecular dynamic approach imposes on our vision of synaptic function the need to incorporate new theoretical frameworks to integrate the cooperative effects between the molecular constituents of the PSD and their regulation, as well as to traverse the scale between the behavior of single molecules and tens-to-hundreds of molecules.