Learning deficits in aged rats related to decrease in extracellular volume and loss of diffusion anisotropy in hippocampus

Proc. Natl. Acad. Sci. U.S.A.

Voříšek

Antonova

et al. 2005

104

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 (α = 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 (α = 0.20 ± 0.01; ADC TMA , 580 ± 16 μm 2 ·s -1 ; ADC W , 618 ± 19 μm 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 μm 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.

Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 99%

Changes in extracellular space size and geometry in APP23 transgenic mice: A model of Alzheimer's disease

Proc. Natl. Acad. Sci. U.S.A.

Voříšek

Antonova

et al. 2005

104

“…These changes, therefore, may be an essential mechanism for physiological functions such as milk ejection and body fluid homeostasis. Astrocytic regulation of diffusion in the ECS could be relevant in other brain regions in which similar physiological neuroglial remodeling has been documented (11,13,29,30). It is highly likely, then, that astrocytes not only influence communication between independent adjacent synapses but, more generally, also constitute a potent regulator of extrasynaptic or volume transmission (12,31) for a variety of active substances including neurotransmitters, peptides, endocannabinoids, or neurosteroids.…”

Section: Discussionmentioning

confidence: 91%

Physiological contribution of the astrocytic environment of neurons to intersynaptic crosstalk

Piet

Vargová

Proc. Natl. Acad. Sci. U.S.A.

et al. 2004

234

173

Interactions between separate synaptic inputs converging on the same target appear to contribute to the fine-tuning of information processing in the central nervous system. Intersynaptic crosstalk is made possible by transmitter spillover from the synaptic cleft and its diffusion over a distance to neighboring synapses. This is the case for glutamate, which inhibits ␥-aminobutyric acid (GABA)ergic transmission in several brain regions through the activation of presynaptic receptors. Such heterosynaptic modulation depends on factors that influence diffusion in the extracellular space (ECS). Because glial cells represent a physical barrier to diffusion and, in addition, are essential for glutamate uptake, we investigated the physiological contribution of the astrocytic environment of neurons to glutamate-mediated intersynaptic communication in the brain. Here we show that the reduced astrocytic coverage of magnocellular neurons occurring in the supraoptic nucleus of lactating rats facilitates diffusion in the ECS, as revealed by tortuosity and volume fraction measurements. Under these conditions, glutamate spillover, monitored through metabotropic glutamate receptor-mediated depression of GABAergic transmission, is greatly enhanced. Conversely, impeding diffusion with dextran largely prevents crosstalk between glutamatergic and GABAergic afferent inputs. Astrocytes, therefore, by hindering diffusion in the ECS, regulate intersynaptic communication between neighboring synapses and, probably, overall volume transmission in the brain.

“…Similarly, during postnatal myelination of rat white matter (corpus callosum), a decrease in a and the establishment of anisotropy corresponds with the period of myelination [22]. In the dentate gyrus of the rat hippocampus, ageing results in a decline in a value, while the averaged l value slightly decreases [29]. Moreover, anisotropy disappears, which is presumably due to the loss of the typical parallel organization of astrocytic processes.…”

Section: (A) Transient Changesmentioning

confidence: 99%

Astrocytes and extracellular matrix in extrasynaptic volume transmission

Vargová

2014

Phil. Trans. R. Soc. B

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 a, and the presence of diffusion barriers, reflected by tortuosity l, 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.