Lateral Diffusion Drives Constitutive Exchange of AMPA Receptors at Dendritic Spines and Is Regulated by Spine Morphology

Abstract

Synapse specificity is a basic feature of synaptic plasticity, but it remains unclear how synapse-specific signaling is achieved if postsynaptic membrane proteins can diffuse laterally between synapses. We monitored movements of AMPA receptors (AMPARs) on the surface of mature neurons to investigate the role of lateral diffusion in constitutive AMPAR trafficking and to assess the influence of membrane architecture on the surface distribution of synaptic proteins. Our data show that lateral diffusion is responsible for the continual exchange of a substantial pool of AMPARs at the spine surface. Furthermore, we found that a general characteristic of membrane proteins is that their movement into and out of spines is slow compared with that in nonspiny membrane. This shows that lateral diffusion is dependent on spine morphology and is restricted at the spine neck. These results demonstrate the importance of lateral diffusion in trafficking of AMPAR protein population and provide new insight into how spine structure can maintain synapse specificity by compartmentalizing lateral diffusion and therefore increasing the residence time of membrane proteins near individual synapses.

Stochastic models of intracellular transport

“…(This rate depends on the detailed geometry of the dendritic spine (Ashby et al, 2006)). It is assumed that surface receptors within the jth spine can be recycled with respect to the intracellular pool with k, σ the rates of endocytosis and exocytosis, respectively.…”

“…In particular, the diffusivity is reduced by increasing the ratio k/σ of the rates of endocytosis and exocytosis or by increasing the surface area A of a spine relative to the product of the spine spacing d and circumference of the cable l. Interestingly, D does not depend on the hopping rate Ω. Taking typical measured values of the diffusivity (D = 0.1µm 2 s −1 ) (Ashby et al, 2006;Groc et al, 2004), the area of a spine (A = 1µm 2 ), the spacing between spines (d = 1µm) and the circumference of a dendrite (l = 1µm) (Sorra and Harris, 2000), it follows that D ef f = 0.5D when k = σ, whereas D D 0 when k σ. There is experimental evidence that the rates of exo/endocytsosis are activitydependent (Ehlers et al, 2007) so that the ratio k/σ, and hence D, may be modifiable by experience.…”

Enhanced Glutamatergic Synaptic Plasticity in the Hippocampal CA1 Field of Food-Restricted Rats: Involvement of CB1 Receptors

“…Mushroom spines are known to regulate the diffusion of membrane-associated ions and proteins (Hugel et al, 2009) and AMPA receptors (Ashby et al, 2006), making the glutamatergic synapse highly responsive to Ca 2+ signaling involved in LTP formation (Schmidt and Eilers, 2009). Thus, mushroom spines are considered to be involved in the mechanisms of already acquired information sustaining memory storage (Bourne and Harris, 2007).…”

Regulation of AMPA receptors and synaptic plasticity

“…Stimulation of synaptic NMDA receptors under conditions that raise the strength of glutamatergic synapses increased the mobile fraction of receptors but a slower kinetics for spine GluR1 was observed (Sharma et al, 2006). Other FRAP and fluorescence loss in photobleaching (FLIP) studies in cultured hippocampal neurons expressing SEP-GluR2 unraveled a population of surface receptors that continually move in and out of the dendritic spine by lateral diffusion, and showed a barrier to AMPAR lateral movement located at the spine neck (Ashby et al, 2006).…”

“…The role of lateral diffusion in AMPAR trafficking has recently been investigated using novel methods that allow single receptor monitoring (Borgdorff and Choquet, 2002;Tardin et al, 2003;Groc et al, 2004;Bats et al, 2007;Ehlers et al, 2007), but also by FRAP (Ashby et al, 2006;Sharma et al, 2006;Bats et al, 2007). The initial studies used latex particles coated with an antibody against the extracellular domain of GluR2 (Borgdorff and Choquet, 2002) and were followed by single-molecule fluorescence imaging experiments [using organic dyes or semiconductor quantum dots; (Tardin et al, 2003;Groc et al, 2004;Bats et al, 2007;Ehlers et al, 2007)].…”