Biology subjects

Holcman, D.

Publications and source records attributed to Holcman, D..

8 recordsLinked to original sources

bioRxiv2018

The first one hundred nanometers inside the pre-synaptic terminal where calcium diffusion triggers vesicular release

Calcium diffusion in the thin one hundred nanometers layer located between the plasma membrane and docked vesicles in the pre-synaptic terminal of neuronal cells mediates vesicular fusion and synaptic transmission. Accounting for the narrow-cusp geometry located underneath the vesicle is a key ingredient that defines the probability and the time scale of calcium diffusion to bind calcium sensors for the initiation of vesicular release. We study here the time scale, the calcium binding dynamics and the consequences for asynchronous versus synchronous release. To conclude, threedimensional modeling approaches and the associated coarse-grained simulations can now account efficiently for the precise co-organization of vesicles and Voltage-Gated-Calcium-Channel (VGCC). This co-organization is a key determinant of short-term plasticity and it shapes asynchronous release. Moreover, changing the location of VGCC from few nanometers underneath the vesicle modifies significantly the release probability. Finally, by modifying the calcium buffer concentration, a single synapse can switch from facilitation to depression.

biophysics↗

bioRxiv2018

Dynamics of ion fluxes between neurons, astrocytes and the extracellular space during neurotransmission

Ionic homeostasis in the brain involves redistribution of ionic fluxes in several cell types and compartments, including neurons, astrocytes and the extracellular space. How the major ionic activity-dependent fluxes of potassium and sodium are individually regulated remains difficult to dissociate and to track experimentally. We here review recent progress in modeling the ionic fluxes evoked by neuronal activity based on mass conservation. Excitability of neurons indeed relies on inward sodium and outward potassium fluxes during action potential firing. Recently, we have developed a tri-compartment model based on mass-action kinetics equations that account for potassium dynamics between neurons, astrocytes and the extracellular space. This review describes how such type of model can be used to spatially and temporally predict potassium fluxes during various regimes of neuronal activity. In particular, the model initially showed that it takes several seconds for astrocytes to buffer the majority of the potassium rapidly released by neurons in both basal and high regime of activity. Such model can also probe the selective contribution of ionic channels, and revealed for instance that disruption of the main astroglial potassium Kir4.1 channels not only favors the emergence of epileptiform activity, but also dysregulates neuronal excitability specifically during slow rhythmic activities. We here also extend the predictions of the model by assessing the selective contribution of the astroglial and neuronal Na/K ATPase, or volume of the extracellular space on potassium dynamics. We discuss these findings and their implications for neuronal information processing in the healthy and diseased brain.

neuroscience↗

bioRxiv2018

Fast calcium transients in neuronal spines is driven by extreme statistics

Extreme statistics describe the distribution of rare events that can define the timescales of transduction within cellular microdomains. We combine biophysical modeling and analysis of live-cell calcium imaging to explain the fast calcium transient in spines. We show that in the presence of a spine apparatus (SA), which is an extension of the smooth endoplasmic reticulum (ER), calcium transients during synaptic inputs rely on rare and extreme calcium ion trajectories. Using numerical simulations, we predicted the asymmetrical distributions of Ryanodine receptors and SERCA pumps that we confirmed experimentally. When calcium ions are released in the spine head, the fastest ions arriving at the base determine the transient timescale through a calcium-induced calcium release mechanism. In general, the fastest particles arriving at a small target are likely to be a generic mechanism that determines the timescale of molecular transduction in cellular neuroscience.\n\nSignificance statementIntrigued by fast calcium transients of few milliseconds in dendritic spines, we investigated its underlying biophysical mechanism. We show here that it is generated by the diffusion of the fastest calcium ions when the spine contains a Spine Apparatus, an extension of the endoplasmic reticulum. This timescale is modulated by the initial number of released calcium ions and the asymmetric distribution of its associated calcium release associated Ryanodyne receptors, present only at the base of a spine. This novel mechanism of calcium signaling that we have unraveled here is driven by the fastest particles. To conclude, the rate of arrival of the fastest particles (ions) to a small target receptor defines the timescale of activation instead of the classical forward rate of chemical reactions introduced by von Smoluchowski in 1916. Applying this new rate theory to transduction should refine our understanding of the biophysical mechanisms underlying molecular signaling.

cell biology↗

bioRxiv2018

Electrical transient laws in neuronal microdomains based on electro-diffusion

The current-voltage (I-V) conversion characterizes the physiology of cellular microdomains and reflects cellular communication, excitability, and electrical transduction. Yet deriving such I-V laws remains a major challenge in most cellular microdomains due to their small sizes and the difficulty of accessing voltage with a high nanometer precision. We present here novel analytical relations derived for different numbers of ionic species inside a neuronal micro/nano-domains, such as dendritic spines. When a steady-state current is injected, we find a large deviation from the classical Ohms law, showing that the spine neck resistance is insuficent to characterize electrical properties. For a constricted spine neck, modeled by a hyperboloid, we obtain a new I-V law that illustrates the consequences of narrow passages on electrical conduction. Finally, during a fast current transient, the local voltage is modulated by the distance between activated voltage-gated channels. To conclude, electro-diffusion laws can now be used to interpret voltage distribution in neuronal microdomains.

neuroscience↗

bioRxiv2017

Heterogeneous cross-linked polymers to reconstruct chromatin reorganization during cell differentiation

Chromatin of mammalian nucleus folds into discrete contact enriched regions such as Topologically Associating domains (TADs). The folding hierarchy of the TADs and their internal organization is highly dynamic through cellular differentiation, where structural changes within and between TADs are correlated with gene activation and silencing. To account for multiple interacting TADs, we developed a parsimonious randomly cross-linked (RCL) polymer model that maps high frequency encounters present in HiC data within and between TADs into direct local monomer interactions, characterized by the number of cross-links at a given base-pair resolution. We reconstruct three TADs obtained from the mammalian X chromosome for three stages of differentiation. We compute the radius of gyration of TADs and the encounter probability between genomic segments. We found 1) a synchronous compaction and decompaction of TADs throughout differentiation and 2) secondary structures such as meta-TADs in 5C data resulting from weak inter-TAD interactions. Finally, the present method links steady-state to dynamic properties of the chromatin revealed by the distribution of anomalous exponents of single loci trajectories, reconstructed from HiC data.

genomics↗

bioRxiv2017

Redundancy principle for optimal random search in biology

Chemical activation rate is traditionally determined by the diffusion flux into an absorbing ball, as computed by Smoluchowski in 1916. Thus the rate is set by the mean first passage time (MFPT) of a Brownian particle to a small target. This paradigm is shifted in this manuscript to set the time scale of activation in cellular biology to the mean time of the first among many arrivals of particles at the activation site. This rate is very different from the MFPT and depends on different geometrical parameters. The shift calls for the reconsideration of physical modeling such as deterministic and stochastic chemical reactions based on the traditional forward rate, especially for fast activation processes occurring in living cells. Consequently, the biological activation time is not necessarily exponential. The new paradigm clarifies the role of population redundancy in accelerating search processes and in defining cellular-activation time scales. This is the case, for example, in cellular transduction or in the nonlinear dependence of fertilization rate on the number of spermatozoa. We conclude that statistics of the extreme set the new laws of biology, which can be very different from the physical laws derived for individuals.

biophysics↗

bioRxiv2017

Two Loci Single Particle Trajectories Analysis: Constructing A First Passage Time Statistics Of Local Chromatin Exploration

Stochastic single particle trajectories are used to explore the local chromatin organization. We present here a statistical analysis of the first contact time distributions between two tagged loci recorded experimentally. First, we extract the association and dissociation times from data for various genomic distances between loci and we show that the looping time occurs in confined nanometer regions. Second, we characterize the looping time distribution for two loci in the presence of multiple DNA damages. Finally, we construct a polymer model that accounts for the local chromatin organization before and after a double-stranded DNA break (DSB) to estimate the level of chromatin decompaction. This novel passage time statistics method allows extracting transient dynamic at scales from one to few hundreds of nanometers, predicts the local changes in the number of binding molecules following DSB and can be used to better characterize the local dynamic of the chromatin.

biophysics↗

bioRxiv2016

Electro-diffusion modulation of synaptic input in dendritic spines using deconvolved voltage sensor time series

The inward current flowing inside the post-synaptic terminal of a neuron modulates transiently the membrane voltage potential. Most of the excitatory connections are made on dendritic spines characterized by a large variability in their geometry.How the voltage in a spine is modulated by geometry remains elusive due in part to the absence of direct measurements. To understand the spine voltage-current relation, we develop here a model for the voltage and we use it to extract electrical properties from live cell imaging data. We first deconvolve the genetically encoded voltage sensor expressed in hippocampal neurons and then use electro-diffusion theory, to compute the electric field and the ionic flows induced in a dendritic spine.The ionic flow is driven by the electric field coupled to the charge densities that interact through the non-cylindrical spine geometry. We determine the I-V relation and conclude that the spine effective resistance is mostly determined by the neck geometry. This modulation of synaptic inputs by the spine neck is significantly larger than what was expected from traditional cable models. Thus modulating the postsynaptic current can be achieved by changing the number of receptors or by altering the spine geometry which independently affects the transformation of current into voltage.\n\nSignificance statementDendritic spines are geometrical structures receiving most of the excitatory transmission, yet how they modulate voltage from the synaptic current is not clear due to their submicron small size and specific non-cylindrical geometry. We study here the conversion of the synaptic current into voltage modulated by the spine geometry. Our approach is based on the electro-diffusion theory and we show that the spine neck is the main resistance filter, while the voltage is maintained constant in the head. Finally, we extract the effective resistance using a deconvolution of the genetically encoded voltage indicators expressed in hippocampal neurons. The present approach allows studying the electrical properties of many other structures such as glial small protrusions, cilia, and many others.

neuroscience↗