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.

• Keywords
• astrocytes, diffusion, extracellular matrix, extracellular space, tortuosity, volume fraction,
• MeSH
• Anisotropy MeSH
• Astrocytes pathology   MeSH
• Diffusion MeSH
• Extracellular Matrix physiology   MeSH
• Humans MeSH
• Cell Communication physiology   MeSH
• Synaptic Transmission physiology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

To understand the structural alterations that underlie early and late changes in hippocampal diffusivity after hypoxia/ischemia (H/I), the changes in apparent diffusion coefficient of water (ADC(W)) were studied in 8-week-old rats after H/I using diffusion-weighted magnetic resonance imaging (DW-MRI). In the hippocampal CA1 region, ADC(W) analyses were performed during 6 months of reperfusion and compared with alterations in cell number/cell-type composition, glial morphology, and extracellular space (ECS) diffusion parameters obtained by the real-time iontophoretic method. In the early phases of reperfusion (1 to 3 days) neuronal cell death, glial proliferation, and developing gliosis were accompanied by an ADC(W) decrease and tortuosity increase. Interestingly, ECS volume fraction was decreased only first day after H/I. In the late phases of reperfusion (starting 1 month after H/I), when the CA1 region consisted mainly of microglia, astrocytes, and NG2-glia with markedly altered morphology, ADC(W), ECS volume fraction and tortuosity were increased. Three-dimensional confocal morphometry revealed enlarged astrocytes and shrunken NG2-glia, and in both the contribution of cell soma/processes to total cell volume was markedly increased/decreased. In summary, the ADC(W) increase in the CA1 region underlain by altered cellular composition and glial morphology suggests that considerable changes in extracellular signal transmission might occur in the late phases of reperfusion after H/I.

• MeSH
• Astrocytes pathology   MeSH
• Cell Death MeSH
• Time Factors MeSH
• Diffusion MeSH
• Diffusion Magnetic Resonance Imaging MeSH
• Extracellular Space metabolism   MeSH
• Gliosis etiology   pathology   MeSH
• CA1 Region, Hippocampal pathology   physiopathology   MeSH
• Hypoxia complications   pathology   physiopathology   MeSH
• Immunohistochemistry MeSH
• Brain Ischemia complications   pathology   physiopathology   MeSH
• Microscopy, Confocal MeSH
• Rats MeSH
• Neuroglia pathology   MeSH
• Cell Count MeSH
• Rats, Wistar MeSH
• Cell Proliferation * MeSH
• Reperfusion MeSH
• Body Water metabolism   MeSH
• Imaging, Three-Dimensional MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study 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
• Diffusion MeSH
• Extracellular Space chemistry   diagnostic imaging   physiology   MeSH
• Quaternary Ammonium Compounds MeSH
• Humans MeSH
• Brain Chemistry physiology   MeSH
• Brain cytology   physiology   MeSH
• Neuroglia physiology   MeSH
• Neurons physiology   MeSH
• Radionuclide Imaging MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Quaternary Ammonium Compounds MeSH
• tetramethylammonium MeSH Browser

Diffusion parameters of the extracellular space (ECS) are changed in many brain pathologies, disturbing synaptic as well as extrasynaptic "volume" transmission, which is based on the diffusion of neuroactive substances in the ECS. Amyloid deposition, neuronal loss, and disturbed synaptic transmission are considered to be the main causes of Alzheimer's disease dementia. We studied diffusion parameters in the cerebral cortex of transgenic APP23 mice, which develop a pathology similar to Alzheimer's disease. The real-time tetramethylammonium (TMA) method and diffusion-weighted MRI were used to measure the ECS volume fraction (alpha = ECS volume/total tissue volume) and the apparent diffusion coefficients (ADCs) of TMA (ADC(TMA)), diffusing exclusively in the ECS and of water (ADC(W)). Measurements were performed in vivo in 6-, 8-, and 17- to 25-month-old hemizygous APP23 male and female mice and age-matched controls. In all 6- to 8-month-old APP23 mice, the mean ECS volume fraction, ADC(TMA), and ADC(W) were not significantly different from age-matched controls (alpha = 0.20 +/- 0.01; ADC(TMA), 580 +/- 16 microm(2).s(-1); ADC(W), 618 +/- 19 microm(2).s(-1)). Aging in 17- to 25-month-old controls was accompanied by a decrease in ECS volume fraction and ADC(W), significantly greater in females than in males, but no changes in ADC(TMA). ECS volume fraction increased (0.22 +/- 0.01) and ADC(TMA) decreased (560 +/- 7 microm(2).s(-1)) in aged APP23 mice. The impaired navigation observed in these animals in the Morris water maze correlated with their plaque load, which was twice as high in females (20%) as in males (10%) and may, together with changed ECS diffusion properties, account for the impaired extrasynaptic transmission and spatial cognition observed in old transgenic females.

• MeSH
• Alzheimer Disease etiology   MeSH
• Amyloid beta-Protein Precursor genetics   physiology   MeSH
• Diffusion MeSH
• Extracellular Space metabolism   MeSH
• Quaternary Ammonium Compounds metabolism   MeSH
• Magnetic Resonance Imaging MeSH
• Disease Models, Animal * MeSH
• Mice, Transgenic MeSH
• Mice MeSH
• Aging pathology   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Amyloid beta-Protein Precursor MeSH
• Quaternary Ammonium Compounds MeSH
• tetramethylammonium MeSH Browser