Self-assembly and plasticity of synaptic domains through a reaction-diffusion mechanism

Abstract

Signal transmission across chemical synapses relies crucially on neurotransmitter receptor molecules, concentrated in postsynaptic membrane domains along with scaffold and other postsynaptic molecules. The strength of the transmitted signal depends on the number of receptor molecules in postsynaptic domains, and activity-induced variation in the receptor number is one of the mechanisms of postsynaptic plasticity. Recent experiments have demonstrated that the reaction and diffusion properties of receptors and scaffolds at the membrane, alone, yield spontaneous formation of receptor-scaffold domains of the stable characteristic size observed in neurons. On the basis of these experiments we develop a model describing synaptic receptor domains in terms of the underlying reaction-diffusion processes. Our model predicts that the spontaneous formation of receptor-scaffold domains of the stable characteristic size observed in experiments depends on a few key reactions between receptors and scaffolds. Furthermore, our model suggests novel mechanisms for the alignment of preand postsynaptic domains and for short-term postsynaptic plasticity in receptor number. We predict that synaptic receptor domains localize in membrane regions with an increased receptor diffusion coefficient or a decreased scaffold diffusion coefficient. Similarly, we find that activity-dependent increases or decreases in receptor or scaffold diffusion yield a transient increase in the number of receptor molecules concentrated in postsynaptic domains. Thus, the proposed reaction-diffusion model puts forth a coherent set of biophysical mechanisms for the formation, stability, and plasticity of molecular domains on the postsynaptic membrane.

Distribution of randomly diffusing particles in inhomogeneous media

“…In particular, the DLEs derived here suggest that the average steady-state concentration of particles in each domain is independent of the arrangement and shape of domains. While we have focused here on the deterministic parts of the lattice Langevin equations associated with diffusion in inhomogeneous media, the formalism employed here can be extended [24,33,34,[38][39][40][41][42] to carry out a systematic analysis of the fluctuations induced by the random hopping of particles in inhomogeneous media, and to connect the DLEs derived here to generalized diffusion equations with spatially-varying diffusion coefficients [16][17][18][19][20][21]25].…”

“…+ is the only physically relevant solution (see below), which yields φ (2) via Eq. (20), and hence F (s.s.) 1,2 through Eq. (11):…”

“…Following the approach in Refs. [19,20,[24][25][26][27] we transform the ME (3) into the more tractable lattice Langevin equations…”

“…For instance, if the steric constraints in the system are non-uniform, different f i (x) may need to be used for different lattice sites. We focus here on the most straightforward choice of a uniform f i (x) = x that has previously been successfully employed in the context of population biology [32][33][34], protein diffusion in crowded cell membranes [20][21][22]25], and general models of non-Fickian diffusion [35,36]. We first consider, in Secs.…”

Spatially compartmentalized phase regulation of a Ca2+-cAMP-PKA oscillatory circuit

“…This could allow spatial instabilities like those seen in (Haselwandter et al 2015) used to describe post synaptic domains. The final Gaussian profile on the top boundary had the size of the domain and Gaussian profile informed by STORM images of AC clustering (Figure 3).…”