# Diffusion laws in dendritic spines

- David Holcman
^{1, 2}Email author and - Zeev Schuss
^{3}

**1**:10

https://doi.org/10.1186/2190-8567-1-10

© Holcman and Schuss; licensee Springer. 2011

**Received: **1 August 2011

**Accepted: **27 October 2011

**Published: **27 October 2011

## Abstract

Dendritic spines are small protrusions on a neuronal dendrite that are the main locus of excitatory synaptic connections. Although their geometry is variable over time and along the dendrite, they typically consist of a relatively large head connected to the dendritic shaft by a narrow cylindrical neck. The surface of the head is connected smoothly by a funnel or non-smoothly to the narrow neck, whose end absorbs the particles at the dendrite. We demonstrate here how the geometry of the neuronal spine can control diffusion and ultimately synaptic processes. We show that the mean residence time of a Brownian particle, such as an ion or molecule inside the spine, and of a receptor on its membrane, prior to absorption at the dendritic shaft depends strongly on the curvature of the connection of the spine head to the neck and on the neck's length. The analytical results solve the narrow escape problem for domains with long narrow necks.

## Keywords

## 1 Introduction

Change of spine morphology can be induced by synaptic potentiation protocols [13–15] and indeed intracellular signaling such as calcium released from stores alters the morphology of dendritic spines in cultured hippocampal neurons. These changes in geometry can affect the spine-dendrite communication. One of the first quantitative assessment of geometry was obtained by a direct measurement [16] of diffusion though the spine neck. Using photobleaching and photorelease of fluorescein dextran, by generating concentration gradients between spines and shafts in rat CA1 pyramidal neurons, the time course of re-equilibration was well approximated by a single exponential decay, with a time constant in the range of 20 to 100 ms. The role of the spine neck was further investigated using flash photolysis of caged calcium [3, 17] and theory [18], and the main conclusion was that geometrical changes in the spine neck such as the length or the radius are key modulator of the spine-dendrite communication [12, 19, 20], affecting calcium dynamics. However, in all these studies, the nature of the connection between the neck and head was not considered. The theoretical studies [19, 21] considered non-smooth connection only of the head to the narrow cylindrical neck (Figure 1) and did not account for any effect of curvature. This is precisely the goal of this article to investigate the consequences of this connection.

The connection between the head and the neck is not only relevant for the three-dimensional diffusion, but also essential to the analysis of other synaptic properties. Indeed, synaptic transmission and plasticity involve the trafficking of receptors [22–27] such as AMPA or NMDA receptors (AMPARs or NMDARs) that mediate the glutamatergic-induced synaptic current. Single particle approaches have further [28, 29] revealed the heterogeneity of two-dimensional trajectories occurring on the neuron surface, suggesting that there are several biophysical processes involved in regulating the receptor motion. In addition, the number and type of receptors that shape the synaptic current [23] could be regulated by the spine geometry. This question was further explored theoretically [30, 31], using asymptotic expressions for the residence time and experimentally [32] by monitoring the movements of AMPARs on the surface of mature neurons using FRAP. Employing a combination of confocal microscopy and photobleaching techniques in living hippocampal CA1 pyramidal neurons, a correlation between spine shape parameters and the diffusion and compartmentalization of membrane-associated proteins was recently confirmed [33]. Lateral diffusion seems to be a constitutive process of AMPAR trafficking; it depends on spine morphology and is restricted by the spine geometry [34].

_{1}and a narrow cylindrical neck of cross section |∂Ω

_{ a }and length

*L*(see Figure 2). Our connection formula is given as

The connection between the two parts in the context of the NET problem was attempted in [21, 35] for the oversimplified model of a discontinuous connection. Here, we study a large class of connections and reveal the role of curvature in the spine-neck connection in regulating diffusion flux through narrow necks. More specifically, we study here the residence time of a Brownian particle from the spine head to the absorbing end of the spine neck moving either on the surface or inside the spine. We use the results of [36, 37] for the mean first passage time (MFPT) to an absorbing boundary at the end of a cusp-shaped protrusion in the head. They account for the effects of curvature generated by the neck-head connection in the spine. The reciprocal of the MFPT is the rate of arrival (probability flux) of Brownian particles from the head to the dendrite [38]. We calculate the narrow escape time (NET) from spine-shaped domains with heads connected smoothly and non-smoothly to the neck.

## 2 The NET from a domain with a bottleneck

We consider two- and three-dimensional composite domains Ω that consist of a head Ω_{1} connected through a small interface ∂Ω *i*to a narrow cylindrical neck Ω_{2}. The boundary of Ω is assumed reflecting to Brownian particles, except the far end of Ω_{2}, denoted ∂Ω_{a}, which is absorbing. For example, in Figure 2, the interface ∂Ω _{
i
} is the black segment AB and the absorbing boundary ∂Ω _{
a
} is the segment CD at the bottom of the strip. The NET from such a composite domain cannot be calculated by the methods of [39–42], because the contribution of the singular part of Neumann's function to the MFPT in a composite domain with a funnel or another bottleneck is not necessarily dominant. The method of matched asymptotic expansions requires different boundary or internal layers at a cusp-like absorbing window than at an absorbing window which is cut from a smooth reflecting boundary (see [43–46]). The methods used in [21, 35] for constructing the MFPT in a composite domain of the type shown in Figure 1d are made precise here and the new method extends to the domains of the type shown in Figure 1c.

First, we recount some basic facts about the NET [35, 39–41, 43–45, 47, 48]. The NET is the MFPT of a Brownian trajectory to a small absorbing part of the boundary of a domain, whose remaining boundary reflects Brownian trajectories. Refined asymptotic formulas for the NET were derived in [42, 46, 49, 50], and were used to estimated chemical reaction rates.

*t*) in a sufficiently regular bounded domain Ω, whose boundary ∂Ω consists of a reflecting part ∂Ω

_{ r }and an absorbing part ∂Ω

_{a}. The expected lifetime of x(

*t*) in Ω, given x(0) = x∈ Ω, is the MFPT

*v*(x) of x(

*t*) from x to ∂Ω

_{ a }is the solution of the mixed boundary value problem [38]

*v*(x)/∂

*n*is the normal derivative at the boundary point x. If the size of the absorbing part ∂Ω

_{ a }of the boundary is much smaller than the reflecting part ∂Ω

_{r}, the MFPT $\stackrel{\u0304}{\tau}=v\left(\mathit{x}\right)$ is to leading order independent of x∈ Ω

_{ a }and can be represented by the Neumann function

*N*(x, y) as

_{ a }outside a boundary layer near ∂Ω

_{a}. The Neumann function is a solution of the boundary value problem

and is defined up to an additive constant [39, 47].

### 2.1 The MFPT from the head to the interface

_{ i }is an absorbing window cut from the smooth reflecting boundary of Ω

_{1}, as in Figure 1d. The MFPT ${\stackrel{\u0304}{\tau}}_{\mathit{x}\to \partial {\Omega}_{i}}$ is the NET from the reflecting domain Ω

_{1}to the small interface ∂Ω

_{ i }(of length

*a*), such that

*ε*=

*π*|∂Ω

_{i}|/|∂Ω

_{1}| =

*πa*/|∂Ω

_{1}| << 1 (this corrects the definition in [40]). It is given by

_{1}is a disk of radius

*R*, then for x= the center of the disk,

_{ i }(of length

*a*) is located at an algebraic cusp with radius of curvature

*R*

_{ c }(see Figures 1c and 2), the MFPT is given in [36, 37] as

_{1}is a sphere of radius

*R*centered at the origin, connected to Ω

_{2}by a circle ∂Ω

_{ i }centered on the north-south axis near the south pole, with small radius

*a*=

*R*sin

*δ*/2. The domain Ω

_{2}is a right cylinder of radius

*a*connected to Ω

_{1}at ∂Ω

_{i}, and the absorbing boundary ∂Ω

_{ a }is the circle of radius

*a*at the bottom of the cylinder. The MFPT from Ω

_{1}to ∂Ω

_{ i }is given in [37, 41, 51–53] as

where *θ* is the angle between x and the south-north axis of the sphere.

*ε*can be represented parametrically as

*z*-axis with

*z*= 0 at the top of the surface and

*z*= Λ at the end of the funnel,

*r*is distance to the

*z*-axis, and

*r*=

*r*(

*z*) is the equation of the generating curve. We have

*ℓ*has dimension of length. For

*α*= 1 the parameter

*ℓ*is related to the radius of curvature

*R*

_{ c }at

*z*= Λ by

*ℓ*= 2

*R*

_{ c }. For

*α*> 0 [37]

_{1}| is the entire area of the surface. In particular, for

*α*= 1 we get the MFPT

The case *α* = 0 corresponds to a circular cap of a small radius *a* cut from a closed surface.

_{1}to a disk ∂Ω

_{ i }of small radius

*a*near the south pole is given by [42]

_{1}the MFPT to a circular cap ∂Ω

_{ i }cut from a smooth boundary is given by [42]

where *L*_{
x
} , *R*_{
x
} are the principal curvatures at a point x, and |∂Ω_{i}| = *πa*^{2} is the area of the circular cap.

_{ i }is a circular disk of radius

*a*at the end of an axisymmetric solid funnel, the MFPT is drastically affected and changes to

where *R*_{
c
} is the radius of curvature at the end of the funnel [37].

## 3 Connecting a head to a narrow neck

_{1}, and a narrow neck Ω

_{2}, which is a right circular or planar cylinder of length

*L*, perpendicular to the boundary ∂Ω

_{1}, and of radius

*a*(see Figure 2). Thus, the interface ∂Ω

_{ i }between the head and the neck is a line segment, a circle, or a circular disk, depending on the dimension. We assume that ∂Ω

_{1}- ∂Ω

_{ i }is reflecting and that the other basis of the neck, ∂Ω

_{ a }⊂ ∂Ω

_{2}, is absorbing for the Brownian motion. The length (or area) |∂Ω

_{i}| is given by

where the MFPT ${\stackrel{\u0304}{\tau}}_{\partial {\Omega}_{i}\to \partial {\Omega}_{a}}$ is ${\stackrel{\u0304}{\tau}}_{\mathit{x}\to \partial \Omega a}$, averaged over ∂Ω _{
i
} with respect to the flux density of Brownian trajectories in Ω_{1} into an absorbing boundary at ∂Ω _{
i
} (see [38] for further details).

_{2}the boundary value problem (2)-(4) can be approximated by the one-dimensional boundary value problem

*u*(

*L*) =

*u*

_{ H }is yet unknown. The solution is given by

*B*and

*u*

_{ H }. The constant

*B*is found by multiplying Equation 2 by the Neumann function

*N*(x, y), integrating over Ω

_{1}, applying Green's formula, and using the boundary conditions (3) and (4). Specifically, we obtain for all y∈ ∂Ω

_{i}

*v*(y) ≈

*u*(

*L*) and using (23), we obtain

*v*(x) is the solution of the boundary value problem (2)-(4) in the entire domain Ω = Ω

_{1}⋃ Ω

_{2}, the meaning of (25) is the connecting rule (21), where

Equation 26 gives the MFPT, averaged over Ω_{1}. The averaging is a valid approximation, because the MFPT to ∂Ω _{
i
} is constant to begin with (except in a negligible boundary layer). Equation 27 is the MFPT from the interface to the absorbing end ∂Ω _{
a
} of the strip, and (28) follows from (5).

_{1}and Ω

_{2}continuously across ∂Ω

_{i}, we obtain the total flux on ∂Ω

_{ i }as

*v*(x)/∂

*n*= -

*u*'(0) = -

*B*, we get from (20) and (29) that

The MFPT ${\stackrel{\u0304}{\tau}}_{\mathit{x}\to \partial {\Omega}_{i}}$ is given by (8)-(19) above.

### 3.1 The NET from two- and three-dimensional domains with bottlenecks

_{1}and a narrow cylindrical neck Ω

_{2}of length

*L*and radius

*a*. The radius of curvature at the bottleneck in smooth connecting funnel is

*R*

_{ c }. In the two-dimensional case

where *R* is the radius of the sphere, *a* = *R* sin *δ*/2, and *θ* is the initial elevation angle on the sphere. If |Ω_{1}| >> *aL* and *L* >> *a*, the last term in (32) is dominant, which is the manifestation of the many returns of Brownian motion from the neck to the head prior to absorption at ∂Ω _{
a
} (see an estimate in [19]). The last line of (32) agrees with the explicit calculation in [37].

*πa*

^{2}is given by

*R*

_{ c }is the curvature at the cusp. The order 1 term can be computed for the sphere using the explicit expression of the Neumann-Green function [46]. Figures 4 and 5 show the NET for various parameters, such as the neck length and radius.

Finally, the influence of the neck length on the residence time is shown in Figure 5: changing the neck length modulates dramatically the residence time. Interestingly, the geometry of the connection affects much significantly the dimension two rather than that the three dimensional Brownian motion.

## Discussion and conclusion

We have shown that the mean residence time (or flux) of Brownian particles inside a spine-like structure or on its surface depends strongly on the geometrical properties of both head and neck. Surprisingly, it also depends strongly on the smoothness of the connection between the two.

The application to a freely diffusing AMPA receptor, which is responsible for the excitatory synaptic current, shows that its motion on the spine membrane is strongly restricted by dendritic spine geometry. Our results can be used to estimate the residence time of the receptor on the membrane if interactions with any scaffolding molecules are neglected (the latter are mostly concentrated in a local microdomain called the PSD). Using Equation 32 for non-smooth geometry (Figure 1b) and for a spherical head of radius *R* = 1 *μ* m, a neck length *L* = 1 *μ* m, a neck radius *a* = 0.1 *μ* m, and a diffusion coefficient *D* = 0.1 *μ* m^{2}/*s*, we obtain from the third line of Equation 32 that the residence time is *τ*_{2D}≈ 260 s, while for a smooth connecting geometry (1a) with a curvature radius of *R*_{
c
} = 1 *μ* m at the connecting neck-head *τ*_{2D}≈ 1150 s (line 2 in Equation 32). Evidently, the residence time is more than doubled, leading to the conclusion that there is a significant difference between the function of spines with smoothly and non-smoothly connected necks. We conclude from this analysis that an AMPA receptors that do not interact with the PSD stay on a typical dendritic spine between one and a half to 5 min on average and this residence time is controlled mostly by the geometrical properties of the spine.

We now consider the residence time for freely diffusing particles such as molecules, mRNA, and ions (e.g., calcium) inside a dendritic spine. For a calcium ion, the diffusion constant is about *D*_{ca} = 400 *μ* m^{2}/s [12]. Calcium ions that exit the spine only to the dendrite shaft at the end of the neck, but not through exchangers, give the following residence time estimates. Using formula 33 for a non-smooth connection between the spine head and the neck, we obtain that *τ*_{3D}≈ 195 ms (line 1), while for a smooth connection with radius of curvature 1 *μ* m, the residence time is *τ*_{3D}≈ 820 ms (line 3 in Equation 33). Interestingly, the mean residence time is tripled from the non-smooth to a smooth connection.

A remaining open question is to extend the present analysis to the case where many binding molecules can trap receptors. This effect should be expected to significantly increase the residence time inside a dendritic spine, as has already been observed in [55] for the case of a receptor inside the PSD. The present mathematical analysis of the residence time provides a solution to the narrow escape problem for domains with bottlenecks [21, 35]. Other generalizations of this study is to include the dynamics of many receptors [30, 56] or/and to study dendritic trafficking [57].

There are many other factors that affect the spine-dendrite communication with respect to calcium. This includes calcium pumps, endogenous buffers, calcium stores, the number and rates of exchangers. These mechanisms affect the residence of calcium in spines [58–60] and it would be interesting to add them in the present analysis.

## Declarations

### Acknowledgements

This research was supported by an ERC starting Grant.

## Authors’ Affiliations

## References

- Harris KM, Stevens JK:
**Dendritic spines of rat cerebellar Purkinje cells: serial electron microscopy with reference to their biophysical characteristics.***J Neurosci*1988,**12:**4455–4469.Google Scholar - Bourne JN, Harris KM:
**Balancing structure and function at hippocampal dendritic spines.***Annu Rev Neurosci*2008,**31:**47–67. 10.1146/annurev.neuro.31.060407.125646View ArticleGoogle Scholar - Korkotian E, Holcman D, Segal M:
**Dynamic regulation of spine-dendrite coupling in cultured hippocampal neurons.***Eur J Neurosci*2004,**20**(10):2649–2663. 10.1111/j.1460-9568.2004.03691.xView ArticleGoogle Scholar - Hotulainen P, Hoogenraad CC:
**Actin in dendritic spines: connecting dynamics to function.***J Cell Biol*2010,**189**(4):619–629. 10.1083/jcb.201003008View ArticleGoogle Scholar - Newpher TM, Ehlers MD:
**Spine microdomains for postsynaptic signaling and plasticity.***Trends Cell Biol*2009,**5:**218–227.View ArticleGoogle Scholar - Sheng M, Hoogenraad CC:
**The postsynaptic architecture of excitatory synapses: a more quantitative view.***Annu Rev Biochem*2007,**76:**823–847. 10.1146/annurev.biochem.76.060805.160029View ArticleGoogle Scholar - Crick F:
**Do dendritic spines twitch?***Trends Neurosci*1982,**5:**44–46.View ArticleGoogle Scholar - Filkova E, Delay RJ:
**Cytoplasmic actin in dendritic spines as a possible mediator of synaptic plasticity.***J Cell Biol*1982,**95:**350–365.Google Scholar - Korkotian E, Segal M:
**Spike-associated fast contraction of dendritic spines in cultured hippocampal neurons.***Neuron*2001,**30**(3):751–758. 10.1016/S0896-6273(01)00314-2View ArticleGoogle Scholar - Holcman D, Schuss Z, Korkotian E:
**Calcium dynamic in dendritic spines and spine motility.***Biophys J*2004,**87:**81–91. 10.1529/biophysj.103.035972View ArticleGoogle Scholar - Holcman D, Schuss Z:
**Modeling calcium dynamics in dendritic spines.***SIAM J Appl Math*2005,**65**(3):1006–1026. 10.1137/S003613990342894XMathSciNetView ArticleGoogle Scholar - Holcman D, Korkotian E, Segal M:
**Calcium dynamics in dendritic spines, modeling and experiments.***Cell Calcium*2005,**37**(5):467–475. 10.1016/j.ceca.2005.01.015View ArticleGoogle Scholar - Papa M, Segal M:
**Morphological plasticity in dendritic spines of cultured hippocampal neurons.***Neuroscience*1996,**71**(4):1005–1011. 10.1016/0306-4522(95)00490-4View ArticleGoogle Scholar - Collin C, Miyaguchi K, Segal M:
**Dendritic spine density and LTP induction in cultured hippocampal slices.***J Neurophysiol*1997,**77**(3):1614–1623.Google Scholar - Korkotian E, Segal M:
**Release of calcium from stores alters the morphology of dendritic spines in cultured hippocampal neurons.***Proc Natl Acad Sci USA*1999,**96**(21):12068–12072. 10.1073/pnas.96.21.12068View ArticleGoogle Scholar - Svoboda K, Tank DW, Denk W:
**Direct measurement of coupling between dendritic spines and shafts.***Science*1996,**272**(5262):716–719. 10.1126/science.272.5262.716View ArticleGoogle Scholar - Bloodgood BL, Sabatini BL:
**Neuronal activity regulates diffusion across the neck of dendritic spines.***Science*2005,**310**(5749):866–869. 10.1126/science.1114816View ArticleGoogle Scholar - Holcman D, Marchewka A, Schuss Z:
**Survival probability of diffusion with trapping in cellular neurobiology.***Phys Rev E Stat Nonlinear Soft Matter Phys*2005,**72**(3):031910.View ArticleGoogle Scholar - Biess A, Korkotian E, Holcman D:
**Diffusion in a dendritic spine: the role of geometry.***Phys Rev E Stat Nonlinear Soft Matter Phys*2007,**76:**021922.View ArticleGoogle Scholar - Holcman D, Kupka I:
**Some questions in computational cellular biology.***J Fixed Point Theory Appl*2010,**7**(1):67–83. 10.1007/s11784-010-0012-1MathSciNetView ArticleGoogle Scholar - Berezhkovskii AM, Barzykin AV, Zitserman VY:
**Escape from cavity through narrow tunnel.***J Chem Phys*2009,**130**(24):245104. 10.1063/1.3160546View ArticleGoogle Scholar - Chen L, Chetkovich DM, Petralia RS, Sweeney NT, Kawasaki Y, Wenthold RJ, Bredt DS, Nicoll RA:
**Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms.***Nature*2000,**408:**936. 10.1038/35050030View ArticleGoogle Scholar - Bredt DS, Nicoll RA:
**AMPA receptor trafficking at excitatory synapses.***Neuron*2003,**40:**361. 10.1016/S0896-6273(03)00640-8View ArticleGoogle Scholar - Adesnik H, Nicoll RA, England PM:
**Photoinactivation of native AMPA receptors reveals their real-time trafficking.***Neuron*2005,**48**(6):977–985. 10.1016/j.neuron.2005.11.030View ArticleGoogle Scholar - Shi SH, Hayashi Y, Petralia RS, Zaman SH, Wenthold RJ, Svoboda K, Malinow R:
**Rapid spine delivery and redistribution of AMPA receptors after synaptic NMDA receptor activation.***Science*1999,**284**(5421):1811–1816. 10.1126/science.284.5421.1811View ArticleGoogle Scholar - Malinow R, Malenka RC:
**AMPA receptor trafficking and synaptic plasticity.***Annu Rev Neurosci*2002,**25:**103–126. 10.1146/annurev.neuro.25.112701.142758View ArticleGoogle Scholar - Malinow R:
**AMPA receptor trafficking and long-term potentiation.***Philos Trans R Soc Lond B Biol Sci*2003,**358**(1432):707–714. (Review) (Review) 10.1098/rstb.2002.1233View ArticleGoogle Scholar - Borgdorff AJ, Choquet D:
**Regulation of AMPA receptor lateral movements.***Nature*2002,**417**(6889):649–653. 10.1038/nature00780View ArticleGoogle Scholar - Choquet D, Triller A:
**The role of receptor diffusion in the organization of the postsynaptic membrane.***Nat Rev Neurosci*2003,**4:**251–265.View ArticleGoogle Scholar - Holcman D, Triller A:
**Modeling synaptic dynamics and receptor trafficking.***Biophys J*2006,**91**(7):2405–2415. 10.1529/biophysj.106.081935View ArticleGoogle Scholar - Earnshaw BA, Bressloff PC:
**A biophysical model of AMPA receptor trafficking and its regulation during LTP/LTD.***J Neurosci*2006,**26:**12362–12373. 10.1523/JNEUROSCI.3601-06.2006View ArticleGoogle Scholar - Ashby MC, Maier SR, Nishimune A, Henley JM:
**Lateral diffusion drives constitutive exchange of AMPA receptors at dendritic spines and is regulated by spine morphology.***J Neurosci*2006,**26:**7046. 10.1523/JNEUROSCI.1235-06.2006View ArticleGoogle Scholar - Hugel S, Abegg M, de Paola N, Caroni P, Gähwiler BH, McKinney RA:
**Dendritic spine morphology determines membrane-associated protein exchange between dendritic shafts and spine heads.***Cereb Cortex*2009,**19**(3):697–702. 10.1093/cercor/bhn118View ArticleGoogle Scholar - Makino H, Malinow R:
**AMPA receptor incorporation into synapses during LTP: the role of lateral movement and exocytosis.***Neuron*2009,**64**(3):381–390. 10.1016/j.neuron.2009.08.035View ArticleGoogle Scholar - Schuss Z, Singer A, Holcman D:
**The narrow escape problem for diffusion in cellular microdomains.***Proc Natl Acad Sci USA*2007,**104**(41):16098–16103. 10.1073/pnas.0706599104View ArticleGoogle Scholar - Holcman D, Hoze N, Schuss Z:
**Narrow escape through a funnel and effective diffusion on a crowded membrane.***Phys Rev E*2011,**84:**021906.View ArticleGoogle Scholar - Holcman D, Schuss Z:
**Brownian motion in dire straits: Part I.**2011.Google Scholar - Schuss Z:
*Diffusion and Stochastic Processes: An Analytical Approach*. New York: Springer; 2010.Google Scholar - Singer A, Schuss Z, Holcman D, Eisenberg B:
**Narrow escape I.***J Stat Phys*2006,**122**(3):437–463. 10.1007/s10955-005-8026-6MathSciNetView ArticleGoogle Scholar - Singer A, Schuss Z, Holcman D:
**Narrow escape II.***J Stat Phys*2006,**122**(3):465–489. 10.1007/s10955-005-8027-5MathSciNetView ArticleGoogle Scholar - Singer A, Schuss Z, Holcman D:
**Narrow escape III.***J Stat Phys*2006,**122**(3):491–509. 10.1007/s10955-005-8028-4MathSciNetView ArticleGoogle Scholar - Singer A, Schuss Z, Holcman D:
**Narrow escape and leakage of Brownian particles.***Phys Rev E*2008,**78:**051111.MathSciNetView ArticleGoogle Scholar - Ward MJ, Keller JB:
**Strong localized perturbations of eigenvalue problems.***SIAM J Appl Math*1993,**53:**770–798. 10.1137/0153038MathSciNetView ArticleGoogle Scholar - Ward MJ, Henshaw WD, Keller JB:
**Summing logarithmic expansions for singularly perturbed eigenvalue problems.***SIAM J Appl Math*1993,**53:**799–828. 10.1137/0153039MathSciNetView ArticleGoogle Scholar - Ward MJ, Van De Velde E:
**The onset of thermal runaway in partially insulated or cooled reactors.***IMA J Appl Math*1992,**48:**53–85. 10.1093/imamat/48.1.53MathSciNetView ArticleGoogle Scholar - Cheviakov A, Ward MJ, Straube R:
**An Asymptotic analysis of the mean first passage time for narrow escape problems: Part II: the sphere.***SIAM Multiscale Model Simul*2010,**8**(3):836–870. 10.1137/100782620MathSciNetView ArticleGoogle Scholar - Holcman D, Schuss Z:
**Escape through a small opening: receptor trafficking in a synaptic membrane.***J Stat Phys*2004,**117**(5–6):191–230.MathSciNetView ArticleGoogle Scholar - Kolokolnikov T, Titcombe M, Ward MJ:
**Optimizing the fundamental neumann eigenvalue for the laplacian in a domain with small traps.***Eur J Appl Math*2005,**16:**161–200. 10.1017/S0956792505006145MathSciNetView ArticleGoogle Scholar - Holcman D, Schuss Z:
**Diffusion through a cluster of small windows and flux regulation in microdomains.***Phys Lett A*2008,**372:**3768–3772. 10.1016/j.physleta.2008.02.076View ArticleGoogle Scholar - Holcman D, Schuss Z:
**Diffusion escape through a cluster of small absorbing windows.***J Phys A Math Theoret*2008,**41:**155001. 10.1088/1751-8113/41/15/155001MathSciNetView ArticleGoogle Scholar - Gandolfi A, Gerardi A, Marchetti F:
**Diffusion-controlled reactions in two dimensions.***Acta Applicandae Mathematicae*1985,**4:**139–159. 10.1007/BF00052459MathSciNetView ArticleGoogle Scholar - Linderman J, Laufengerger D:
**Analysis of intracellular receptor/Ligand sorting: calculation of mean surface and bulk diffusion times within a sphere.***Biophys J*1986,**50:**295–305. 10.1016/S0006-3495(86)83463-4View ArticleGoogle Scholar - Coombs D, Straube R, Ward M:
**Diffusion on a sphere with localized traps: mean first passage time, eigenvalue asymptotics, and fekete points.***SIAM J Appl Math*2009,**70**(1):302–332. 10.1137/080733280MathSciNetView ArticleGoogle Scholar - Matkowsky BJ, Schuss Z, Tier C:
**Uniform expansions of the transition rate in Kramers' problem.***J Stat Phys*1984,**35**(3–4):443–456. 10.1007/BF01014395MathSciNetView ArticleGoogle Scholar - Taflia A, Holcman D:
**Dwell time of a Brownian molecule in a microdomain with traps and a small hole on the boundary.***J Chem Phys*2007,**126**(23):234107. 10.1063/1.2746840View ArticleGoogle Scholar - Bressloff PC, Earnshaw BA:
**A dynamical corral model of protein trafficking in spines.***Biophys J*2009,**96:**1786–1802. 10.1016/j.bpj.2008.12.3889View ArticleGoogle Scholar - Bressloff PC:
**Cable theory of protein receptor trafficking in dendritic trees.***Phys Rev E*2009,**79:**041904.MathSciNetView ArticleGoogle Scholar - Majewska A, Brown E, Ross J, Yuste R:
**Mechanisms of calcium decay kinetics in hippocampal spines: role of spine calcium pumps and calcium diffusion through the spine neck in biochemical compartmentalization.***J Neurosci*2000,**20**(5):1722–1734.Google Scholar - Majewska A, Tashiro A, Yuste R:
**Regulation of spine calcium dynamics by rapid spine motility.***J Neurosci*2000,**20**(22):8262–8268.Google Scholar - Yuste R, Majewska A, Holthoff K:
**From form to function: calcium compartmentalization in dendritic spines.***Nat Neurosci*2000,**7:**653–659.View ArticleGoogle Scholar

## Copyright

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.