extracellular diffusion
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Extrasynaptic volume transmission, mediated by the diffusion of neuroactive substances in the extracellular space (ECS), plays an important role in short- and long-distance communication between nerve cells. The ability of a substance to reach extrasynaptic high-affinity receptors via diffusion depends on the ECS diffusion parameters, ECS volume fraction alpha (alpha=ECS volume/total tissue volume) and tortuosity lambda (lambda2=free/apparent diffusion coefficient), which reflects the presence of diffusion barriers represented by, e.g., fine astrocytic processes or extracellular matrix molecules. These barriers channel the migration of molecules in the ECS, so that diffusion may be facilitated in a certain direction, i.e. anisotropic. The diffusion parameters alpha and lambda differ in various brain regions, and diffusion in the CNS is therefore inhomogeneous. Changes in diffusion parameters have been found in many physiological and pathological states, such as development and aging, neuronal activity, lactation, ischemia, brain injury, degenerative diseases, tumor growth and others, in which cell swelling, glial remodeling and extracellular matrix changes are key factors influencing diffusion. Changes in ECS volume, tortuosity and anisotropy significantly affect the accumulation and diffusion of neuroactive substances and thus extrasynaptic transmission, neuron-glia communication, mediator "spillover" and synaptic crosstalk as well as, cell migration. The various changes occurring during pathological states can be important for diagnosis, drug delivery and treatment.
Focal cortical dysplasias (FCDs) of the brain are recognized as a frequent cause of intractable epilepsy. To contribute to the current understanding of the mechanisms of epileptogenesis in FCD, our study provides evidence that not only cellular alterations and synaptic transmission, but also changed diffusion properties of the extracellular space (ECS), induced by modified extracellular matrix (ECM) composition and astrogliosis, might be involved in the generation or spread of seizures in FCD. The composition of the ECM in FCD and non-malformed cortex (in 163 samples from 62 patients) was analyzed immunohistochemically and correlated with the corresponding ECS diffusion parameter values determined with the real-time iontophoretic method in freshly resected cortex (i.e. the ECS volume fraction and the geometrical factor tortuosity, describing the hindrances to diffusion in the ECS). The ECS in FCD was shown to differ from that in non-malformed cortex, mainly by the increased accumulation of certain ECM molecules (tenascin R, tenascin C, and versican) or by their reduced expression (brevican), and by the presence of an increased number of astrocytic processes. The consequent increase of ECS diffusion barriers observed in both FCD type I and II (and, at the same time, the enlargement of the ECS volume in FCD type II) may alter the diffusion of neuroactive substances through the ECS, which mediates one of the important modes of intercellular communication in the brain - extrasynaptic volume transmission. Thus, the changed ECM composition and altered ECS diffusion properties might represent additional factors contributing to epileptogenicity in FCD.
- MeSH
- astrocyty metabolismus MeSH
- brevican analýza MeSH
- difuze MeSH
- dítě MeSH
- dospělí MeSH
- extracelulární matrix chemie metabolismus MeSH
- extracelulární prostor chemie metabolismus MeSH
- iontoforéza metody MeSH
- lidé středního věku MeSH
- lidé MeSH
- malformace mozkové kůry metabolismus patologie MeSH
- mladiství MeSH
- mladý dospělý MeSH
- nemoci mozku metabolismus patologie MeSH
- neokortex patologie MeSH
- předškolní dítě MeSH
- tenascin analýza MeSH
- versikany analýza MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Diffusion in the extracellular space (ECS) of the brain is constrained by the volume fraction and the tortuosity and a modified diffusion equation represents the transport behavior of many molecules in the brain. Deviations from the equation reveal loss of molecules across the blood-brain barrier, through cellular uptake, binding, or other mechanisms. Early diffusion measurements used radiolabeled sucrose and other tracers. Presently, the real-time iontophoresis (RTI) method is employed for small ions and the integrative optical imaging (IOI) method for fluorescent macromolecules, including dextrans or proteins. Theoretical models and simulations of the ECS have explored the influence of ECS geometry, effects of dead-space microdomains, extracellular matrix, and interaction of macromolecules with ECS channels. Extensive experimental studies with the RTI method employing the cation tetramethylammonium (TMA) in normal brain tissue show that the volume fraction of the ECS typically is approximately 20% and the tortuosity is approximately 1.6 (i.e., free diffusion coefficient of TMA is reduced by 2.6), although there are regional variations. These parameters change during development and aging. Diffusion properties have been characterized in several interventions, including brain stimulation, osmotic challenge, and knockout of extracellular matrix components. Measurements have also been made during ischemia, in models of Alzheimer's and Parkinson's diseases, and in human gliomas. Overall, these studies improve our conception of ECS structure and the roles of glia and extracellular matrix in modulating the ECS microenvironment. Knowledge of ECS diffusion properties is valuable in contexts ranging from understanding extrasynaptic volume transmission to the development of paradigms for drug delivery to the brain.
- MeSH
- difuze MeSH
- extracelulární prostor fyziologie chemie MeSH
- financování organizované MeSH
- kvartérní amoniové sloučeniny diagnostické užití MeSH
- lidé MeSH
- mozek - chemie fyziologie MeSH
- mozek cytologie fyziologie MeSH
- neuroglie fyziologie MeSH
- neurony fyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- přehledy MeSH
The structure of brain extracellular space resembles foam. Diffusing molecules execute random movements that cause their collision with membranes and affect their concentration distribution. By measuring this distribution, the volume fraction (alpha) and the tortuosity (lambda) can be estimated. The volume fraction indicates the relative amount of extracellular space and tortuosity is a measure of hindrance of cellular obstructions. Diffusion measurements with molecules <500 Mr show that alpha approximately 0.2 and lambda approximately 1.6, although some brain regions are anisotropic. Molecules > or =3000 Mr show more hindrance, but molecules of 70000 Mr can move through the extracellular space. During stimulation, and in pathophysiological states, alpha and lambda change, for example in severe ischemia alpha = 0.04 and lambda = 2.2. These data support the feasibility of extrasynaptic or volume transmission in the extracellular space.
- MeSH
- corpus callosum ultrastruktura MeSH
- difuze MeSH
- extracelulární prostor * MeSH
- lidé MeSH
- mozek * ultrastruktura MeSH
- mozková kůra ultrastruktura MeSH
- poranění mozku patologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
- Research Support, U.S. Gov't, P.H.S. MeSH
Velikost, geometrie a složení extracelulámího prostoru (ECP) hrají důležitou roli v ovlivňování biologického chováni primárních mozkových nádorů. Pomocí metod, které popisem difuze molekul v ECP umožňují stanovit velikost a geometrii ECP, bylo zjištěno, že velikost ECP je u gliomů významně zvětšená oproti nepostižené mozkové kůře. Dále bylo ukázáno, že zvětšování podílu ECP na celkovém objemu tkáně je přímo úměrné rostoucí proliferační aktivitě astrocytomů a paradoxně i zvyšující se buněčnosti nádorů. Zvětšení objemu ECP ve tkáních mozkových nádorů je překvapivě doprovázeno výrazným nárůstem překážek v difúzi molekul takto zvětšeným mezibuněčným prostorem. Difúzni bariéry v mezibuněčném prostoru astrocytomů s nízkým stupněm malignity vytváří zejména síť z výběžků nádorových buněk. Méně větvené a zkrácené výběžky buněk u agresivnějších astrocytomů hrají menší roli a zmnožení difuzních bariér v ECP působí nadměrná produkce některých komponent extracelulámí matrix (ECM), zejména tenascinu. Nádorem produkované glykoproteiny ECM jsou potom substrátem pro adhezi a migraci nádorových buněk zvětšeným mezibuněčným prostorem, zároveň však mohou výrazně omezovat difúzi léčiv do nádorové tkáně. Mezi přítomnosti tenascinu v ECP nádorů a agresivním chováním gliových nádorů mozku byla nalezena dobrá korelace, což činí imunohistochemický průkaz tohoto glykoproteinu i diagnosticky užitečným jako prognostický marker a ukazatel větší biologické agresivity gliomů.
The size, geometry and composition of the extracellular space (ECS) play an important role in influencing the biological behavior of primary brain tumors. Experiments employing the realtime TMA iontophoretic method to determine the size and geometry of the ECS, by monitoring the diffusion of TMA ions in the ECS, revealed a dramatic increase in ECS size in brain neoplasms when compared with that of unaffected brain cortex. Further, the increase of ECS volume in tumors was shown to correlate with increasing proliferative activity and increasing cellularity of astrocytomas. The increase in ECS size was surprisingly accompanied by a significant increase in diffusion barriers, slowing the diffusion of molecules in the ECS of tumors. In low-grade tumors, diffusion is hindered by the presence of a dense net of tumor cell processes. In high-grade gliomas, in which the cellular processes are shortened with reduced branching, the increase in diffusion barriers is caused by the overproduction of specific components of the extracellular matrix (ECM) by the tumor cells, mainly tenascin. The ECM glycoproteins produced represent a substrate for the subsequent adhesion and migration of tumor cells through the enlarged ECS. However, they might also critically reduce the diffusion of therapeutics into the tumor. The presence of tenascin in the ECS of a neoplasm correlates significantly with the increased malignancy of the tumor and a poor clinical outcome of the disease, thus making the immunohistochemical detection of tenascin diagnostically useful as a prognostic marker and a marker of aggressive biological behavior of tumors.
Extrasynaptický přenos, zprosredkovaný difúzí neur o aktivních látek extracelulárním prostorem (ECP), hraje důležitou úlohu v komunikaci mezi bunkami jak na kratší tak na delší vzdálenost. Schopnost látky navázat se na extrasynaptické receptory s vysokou afinitou závisí na difúzních parametrech ECP, tj. extracelulární objemové frakci α (α = objem ECP/celkový objem tkáně) a tortuozitě λ (λ2 = difúzni koeficient ve volném médiu/aparentní difúzni koeficient ve tkáni), které závisejí na difúzních bariérách tvořených např. výběžky astrocytů či extracelulární matrix. Tyto překážky usměrňují pohyb látek v ECP, a proto je difúze v CNS nejen nehomogenní, ale í v určitém směru usnadněná, tj. anizotropní. Změny difúzních parametrů ECP doprovázejí řadu fyziologických i patologických stavů, ve kterých hrají klíčovou roli strukturání změny gliových buněk a extracelulární matrix. Plastické změny objemu, tortuozity a anizotropie ^xtracelulárního prostoru mohou významně ovlivňovat komunikaci mezi neurony a glií, únik mediátoru ze synaptických štěrbin a vzájemnou komunikaci sousedních synapsí, tzv. synaptický „cross-talk". Změny difúzních parametrů během patologických stavů mohou být důležité v klinické praxi pro stanovení diagnózy, distribuci léčiv do tkáně a průběh samotné léčby.
Extrasynaptic transmission, mediated by the diffusion of neuroactive substances in the extracellular space (ECS), plays an impo rtant role in short- and long-distance communication between nerve cells. The ability of a substance to reach extrasynaptic high-affinity receptors via diffusion depends on the ECS diffusion parameters, i.e. ECS volume fraction ( = ECS volume/total tissue volume) and tortuosity ( 2 = free/apparent diffusion coefficient) reflecting the presence of diffusion barriers represented by, e.g. fine astrocytic process es or extracellular matrix molecules. These barriers channel the migration of molecules in the ECS, so that diffusion in the CNS is inhomogeneous a nd may be facilated in a certain direction, i.e. anisotropic. Changes in diffusion parameters, have been found in many physiological and pathological states in which glial remodeling and extracellular matrix changes are key factors influencing diffusion. Plastic changes in ECS volume , tortuosity and anisotropy signifficantly affect neuron-glia communication, mediator „spillover“ and synaptic cross-talk. The various chang es occuring during pathological states can be important for diagnosis, drug delivery and treatment.
The diffusion of neuroactive substances in the extracellular space (ECS) plays an important role in short- and long-distance communication between nerve cells and is the underlying mechanism of extrasynaptic (volume) transmission. The diffusion properties of the ECS are described by three parameters: 1. ECS volume fraction alpha (alpha=ECS volume/total tissue volume), 2. tortuosity lambda (lambda2=free/apparent diffusion coefficient), reflecting the presence of diffusion barriers represented by, e.g., fine neuronal and glial processes or extracellular matrix molecules and 3. nonspecific uptake k'. These diffusion parameters differ in various brain regions, and diffusion in the CNS is therefore inhomogeneous. Moreover, diffusion barriers may channel the migration of molecules in the ECS, so that diffusion is facilitated in a certain direction, i.e. diffusion in certain brain regions is anisotropic. Changes in the diffusion parameters have been found in many physiological and pathological states in which cell swelling, glial remodeling and extracellular matrix changes are key factors influencing diffusion. Changes in ECS volume, tortuosity and anisotropy significantly affect the accumulation and diffusion of neuroactive substances in the CNS and thus extrasynaptic transmission, neuron-glia communication, transmitter "spillover" and synaptic cross-talk as well as cell migration, drug delivery and treatment.
- MeSH
- anizotropie MeSH
- centrální nervový systém fyziologie MeSH
- difuze MeSH
- extracelulární prostor fyziologie MeSH
- krysa rodu rattus MeSH
- lékové transportní systémy MeSH
- lidé MeSH
- myši transgenní MeSH
- myši MeSH
- neuroglie fyziologie MeSH
- neurony fyziologie MeSH
- pohyb buněk fyziologie MeSH
- signální transdukce fyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Most hypotheses concerning the mechanisms underlying seizure activity in focal cortical dysplasia (FCD) are based on alterations in synaptic transmission and glial dysfunction. However, neurons may also communicate by extrasynaptic transmission, which was recently found to affect epileptiform activity under experimental conditions and which is mediated by the diffusion of neuroactive substances in the extracellular space (ECS). The ECS diffusion parameters were therefore determined using the real-time iontophoretic method in human neocortical tissue samples obtained from surgically treated epileptic patients. The obtained values of the extracellular space volume fraction and tortuosity were then correlated with the histologicaly assessed type of cortical malformation (FCD type I or II). While the extracellular volume remained unchanged (FCD I) or larger (FCD II) than in normal/control tissue, tortuosity was significantly increased in both types of dysplasia, indicating the presence of additional diffusion barriers and compromised diffusion, which might be another factor contributing to the epileptogenicity of FCD.
- MeSH
- dítě MeSH
- dospělí MeSH
- epilepsie patologie MeSH
- extracelulární prostor fyziologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- malformace mozkové kůry patologie MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mozková kůra abnormality patologie MeSH
- neurony patologie fyziologie MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Volume transmission is a form of intercellular communication that does not require synapses; it is based on the diffusion of neuroactive substances across the brain extracellular space (ECS) and their binding to extrasynaptic high-affinity receptors on neurons or glia. Extracellular diffusion is restricted by the limited volume of the ECS, which is described by the ECS volume fraction α, and the presence of diffusion barriers, reflected by tortuosity λ, that are created, for example, by fine astrocytic processes or extracellular matrix (ECM) molecules. Organized astrocytic processes, ECM scaffolds or myelin sheets channel the extracellular diffusion so that it is facilitated in a certain direction, i.e. anisotropic. The diffusion properties of the ECS are profoundly influenced by various processes such as the swelling and morphological rebuilding of astrocytes during either transient or persisting physiological or pathological states, or the remodelling of the ECM in tumorous or epileptogenic tissue, during Alzheimer's disease, after enzymatic treatment or in transgenic animals. The changing diffusion properties of the ECM influence neuron-glia interaction, learning abilities, the extent of neuronal damage and even cell migration. From a clinical point of view, diffusion parameter changes occurring during pathological states could be important for diagnosis, drug delivery and treatment.
- MeSH
- anizotropie MeSH
- astrocyty patologie MeSH
- difuze MeSH
- extracelulární matrix fyziologie MeSH
- lidé MeSH
- mezibuněčná komunikace fyziologie MeSH
- nervový přenos fyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
At the nodes of Ranvier, excitable axon membranes are exposed directly to the extracellular fluid. Cations are accumulated and depleted in the local extracellular nodal region during action potential propagation, but the impact of the extranodal micromilieu on signal propagation still remains unclear. Brain-specific hyaluronan-binding link protein, Bral1, colocalizes and forms complexes with negatively charged extracellular matrix (ECM) proteins, such as versican V2 and brevican, at the nodes of Ranvier in the myelinated white matter. The link protein family, including Bral1, appears to be the linchpin of these hyaluronan-bound ECM complexes. Here we report that the hyaluronan-associated ECM no longer shows a nodal pattern and that CNS nerve conduction is markedly decreased in Bral1-deficient mice even though there were no differences between wild-type and mutant mice in the clustering or transition of ion channels at the nodes or in the tissue morphology around the nodes of Ranvier. However, changes in the extracellular space diffusion parameters, measured by the real-time iontophoretic method and diffusion-weighted magnetic resonance imaging (MRI), suggest a reduction in the diffusion hindrances in the white matter of mutant mice. These findings provide a better understanding of the mechanisms underlying the accumulation of cations due to diffusion barriers around the nodes during saltatory conduction, which further implies the importance of the Bral1-based extramilieu for neuronal conductivity.
- MeSH
- akční potenciály * fyziologie MeSH
- buněčná membrána metabolismus MeSH
- centrální nervový systém * metabolismus ultrastruktura MeSH
- difuze MeSH
- difuzní magnetická rezonance MeSH
- extracelulární matrix metabolismus MeSH
- gating iontového kanálu fyziologie MeSH
- iontové kanály metabolismus MeSH
- kationty metabolismus MeSH
- kyselina hyaluronová metabolismus MeSH
- myši inbrední ICR MeSH
- myši knockoutované MeSH
- myši MeSH
- nervová vlákna myelinizovaná * metabolismus ultrastruktura MeSH
- nervové vedení * fyziologie MeSH
- proteiny nervové tkáně genetika metabolismus MeSH
- proteoglykany genetika metabolismus MeSH
- Ranvierovy zářezy * metabolismus ultrastruktura MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
