Reduced extracellular space in the brain of tenascin‐R‐ and HNK‐1‐sulphotransferase deficient mice
Abstract
Tenascin‐R (TN‐R), a large extracellular glycoprotein, is an important component of the adult brain's extracellular matrix (ECM); tenascin‐C (TN‐C) is expressed mainly during early development, while human natural killer 1 (HNK‐1) is a sulphated carbohydrate epitope that attaches to these molecules, modifying their adhesive properties. To assess their influence on extracellular space (ECS) volume and geometry, we used the real‐time iontophoretic method to measure ECS volume fraction α and tortuosity λ, and diffusion‐weighted magnetic resonance imaging (MRI) to measure the apparent diffusion coefficient of water (ADCW). Measurements were performed in vivo in the cortex and CA1 hippocampal region of TN‐R‐, TN‐C‐ and HNK‐1 sulphotransferase (ST)‐deficient adult mice and their wild‐type littermate controls. In both cortex and hippocampus, the lack of TN‐R or HNK‐1 sulphotransferase resulted in a significant decrease in α and λ. Compared with controls, α in TN‐R–/– and ST–/– mice decreased by 22–26% and 9–15%, respectively. MRI measurements revealed a decreased ADCW in the cortex, hippocampus and thalamus. ADCW reflected the changes in α; the decrease in λ indicated fewer diffusion obstacles in the ECS, presumably due to a decreased macromolecular content. No significant changes were found in TN‐C–/– animals. We conclude that in TN‐R–/– and ST–/– mice, which show morphological, electrophysiological and behavioural abnormalities, the ECS is reduced and its geometry altered. TN‐R, as an important component of the ECM, appears to maintain an optimal distance between cells. The altered diffusion of neuroactive substances in the brain will inevitably affect extrasynaptic transmission, neuron–glia interactions and synaptic efficacy.
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A facilitated diffusion of dissociated FeCl3 due to the lack of PN components most likely accounts for the increased spreading of degeneration in knockout mice.
“On the background of previous reports on the contribution of lecticans40, 41 and TN-R42 to the diffusion and hydration properties of the neural ECM, a facilitated diffusion of dissociated FeCl3 due to the lack of PN components most likely accounts for these effects.”
From Aggrecan, link protein and tenascin-R are essential components of the perineuronal net to protect neurons against iron-induced oxidative stress (2014) · cites this paper as [42]
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Self-citationHNK-1 Carrier Glycoproteins Are Decreased in the Alzheimer’s Disease Brain
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Cicanic, M., Edamatsu, M., Bekku, Y., Voříšek, I., Oohashi, T., & Vargová, L. (2017) · Journal of Neuroscience Research · doi:10.1002/jnr.24136 · Cited by 17 · see citing works
“A previous study in aged mouse cortical tissue (Sykova et al., 2005a) reported an age-related decrease of a values from 0.20 to 0.16 (males) or 0.13 (females) and a decrease in ADCW in males but not in females.”
BackgroundMethodInfluentialSelf-citationSuchá, P., Chmelová, M., Kamenická, M., Bochin, M., Oohashi, T., & Vargová, L. (2019) · Neurochemical Research · doi:10.1007/s11064-019-02894-2 · Cited by 17 · see citing works
“However, PNNs in the MNTB or VPM of KO mice were not completely disrupted, as it was reported in the case of Hapln2 (known also as Bral1) deficient [8] or tenascin-R deficient animals [44], where the ECS diffusion parameters were significantly altered [8, 21].”
McKenna, M., Filteau, J. R., Butler, B., Sluis, K., Chungyoun, M., Schimek, N., & Nance, E. A. (2022) · Journal of Biological Engineering · doi:10.1186/s13036-022-00293-w · Cited by 17 · see citing works
“Changes in brain ECM structure and composition are known to impact the extracellular diffusion of both small molecules [83, 97] and nano-sized probes [19, 98].”
BackgroundThe Molecular Basis of Memory. Part 2: Chemistry of the Tripartite Mechanism
Marx, G. S., & Gilon, C. (2013) · ACS Chemical Neuroscience · doi:10.1021/cn300237r · Cited by 15 · see citing works
Xiao, F., & Hrabětová, S. (2009) · Neuroscience · doi:10.1016/j.neuroscience.2009.03.017 · Cited by 15 · see citing works
“N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript to 1.67 in 3–6 months old mice (Anděrová et al., 2001), 1.47–1.50 in 6–8 months old mice of both genders (Syková et al., 2005a), and 1.52–1.55 in 5–9 months old female mice (Syková et al., 2005b).”
BackgroundInfluentialAllnoch, L., Leitzen, E., Zdora, I., Baumgärtner, W., & Hansmann, F. (2022) · PLoS ONE · doi:10.1371/journal.pone.0270239 · Cited by 14 · see citing works
Extracellular matrix components mark the territories of circumventricular organs
Pócsai, K., & Kálmán, M. (2014) · Neuroscience Letters · doi:10.1016/j.neulet.2014.02.016 · Cited by 14 · see citing works
Cerebral glymphatic system: Structure, regulation, ageing, and mechanisms of encephalopathy
Zhao, D., Wang, J., Zhang, F., Wang, Q., Zang, M., Niu, H., & Tong, Z. (2025) · Ageing Research Reviews · doi:10.1016/j.arr.2025.102986 · Cited by 20 · see citing works
Syková, E., Voříšek, I., Starčuk, Z., Kratochvíla, J., Pavlova, I., Ichikawa, Y., Kwok, J. C. F., Kmonı́čková, E., Myronchenko, S., Hromádka, T., et al. (2025) · Journal of Neuroscience · doi:10.1523/jneurosci.0517-24.2024 · Cited by 13 · see citing works
“In di ff usion-weighted magnetic resonance imaging (DW-MRI) measurements, 10 control rats and 10 rats on the 4-MU diet were subjected to brain and spinal cord imaging after 2 months on their respective diets.”
InfluentialSelf-citationPharmacodynamics of the Glutamate Receptor Antagonists in the Rat Barrel Cortex
Vinokurova, D. A., Zakharov, A., Lebedeva, J., Burkhanova, G., Chernova, K., Lotfullina, N., Khazipov, R., & Valeeva, G. R. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00698 · Cited by 12 · see citing works
“, 2002) and species (Vargova et al., 2003; Sykova et al., 2005; Homola et al., 2006) the diffusion dynamics of glutamate antagonists and other molecules with similar diffusion properties through the rat somatosensory cortex described in the present study are likely to be relevant for the majority of brain regions.”
BackgroundBral1: “Superglue” for the extracellular matrix in the brain white matter
Cicanic, M., Syková, E., & Vargová, L. (2012) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2012.01.009 · Cited by 11 · see citing works
Self-citationBrain Diffusivity and Structural Changes in the R6/2 Mouse Model of Huntington Disease
Voříšek, I., Syka, M., & Vargová, L. (2016) · Journal of Neuroscience Research · doi:10.1002/jnr.23965 · Cited by 10 · see citing works
“This effect might be to some extent compensated for by a loss of extracellular matrix, which is usually related to a decrease (Sykova et al., 2002, 2005b) and by a typical atrophy of HD tissue (Aylward et al., 2004).”
BackgroundMethodSelf-citationBekku, Y., & Oohashi, T. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-981-32-9636-7_8 · Cited by 8 · see citing works
Integrity of White Matter is Compromised in Mice with Hyaluronan Deficiency
Sherpa, A. D., Guilfoyle, D. N., Naik, A. A., Isaković, J., Irie, F., Yamaguchi, Y., Hrabě, J., Aoki, C. J., & Hrabětová, S. (2019) · Neurochemical Research · doi:10.1007/s11064-019-02819-z · Cited by 6 · see citing works
“ECM molecules are important for the preservation of physiologically optimal values of ECS parameters [8, 17, 19] which influence molecular transport through the ECS, namely the extracellular volume fraction and diffusion permeability [20, 21].”
Introduction: Special Issue in Honor of Eva Syková
Abbott, N. J., Nicholson, C., & Verkhratsky, A. (2019) · Neurochemical Research · doi:10.1007/s11064-019-02924-z · Cited by 5 · see citing works
“Eva’s papers have included studies relevant to pain [15], neural injury [16], hypoxia and ischemia [17], experimental autoimmune encephalomyelitis (EAE) [18], X-irradiation [19], aging [20], astrogliosis [21], spreading depression [22], hydrocephalus [23], gliomas [24], Alzheimer’s Disease [25], epilepsy [26] and extr…”
BackgroundDutar, P., & Potier, B. (2018) · Neurochemical Research · doi:10.1007/s11064-018-2677-6 · Cited by 5 · see citing works
Conti, A., Magnin, R., Gerstenmayer, M., Lux, F., Tillement, O., Mériaux, S., Penna, S. D., Romani, G. L., Dumont, E., Bihan, D. L., et al. (2016) · IEEE International Ultrasonics Symposium · doi:10.1109/ultsym.2016.7728773 · Cited by 4 · see citing works
Kálmán, M., Oszwald, E., & Pócsai, K. (2023) · The Journal of Comparative Neurology · doi:10.1002/cne.25470 · Cited by 3 · see citing works
“The rich ECMprovides relatively large intercellular spaces for the diffusion of blood-borne substances (Syková et al., 2005).”
BackgroundBaidoe‐Ansah, D., Carceller, H., Mirzapourdelavar, H., Pérez-Rando, M., Strackeljan, L., Garcia-Vazquez, B., Seidenbecher, C. I., Kaushik, R., Nácher, J., & Dityatev, A. E. (2026) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-026-01762-2 · Cited by 2 · see citing works
“For example, in TnR KO mice, ECM attenuation enhanced reversal learning in the Morris water maze and olfactory discrimination task (Morellini et al., 2010), as well as working memory (Sykova et al., 2005).”
The Pathology of Synapses in Brain Networks Implicated in Depression
Bennett, M. R. (2012) · Springer eBooks · doi:10.1007/978-94-007-5748-6_6 · Cited by 2 · see citing works
Astrocytes in Control of the Biophysical Properties of Extracellular Space
Vargová, L., & Syková, E. (2008) · Springer eBooks · doi:10.1007/978-0-387-79492-1_9 · Cited by 2 · see citing works
“A significant decrease in ECS volume to 12% was found in genetically modified, tenascin-R negative mice ( Sykova et al., 2005a ) . The role of the ECM in determining the ECS volume can also be demonstrated by the changes seen during aging, where a decrease in the amount of CSPG and fibronectin seen in the hippocampus…”
BackgroundSelf-citationSynaptic Changes Responsible for Grey Matter Changes in the Brain of Animal Models Following Stress
Bennett, M. R., & Lagopoulos, J. (2018) · Springer eBooks · doi:10.1007/978-3-319-91116-8_2 · Cited by 1 · see citing works
Control of the Extracellular Ionic Environment and Volume
Syková, E. (2012) · Neuroglia · doi:10.1093/med/9780199794591.003.0034 · Cited by 1 · see citing works
Self-citationExtracellular Matrix Molecules and Formation of CNS Synapses
Ullian, E. M., & Dityatev, A. E. (2006) · Springer eBooks · doi:10.1007/978-0-387-32562-0_12 · Cited by 1 · see citing works
340 Convection-Enhanced Delivery of Macromolecules to the Brain Using Electrokinetic Transport
Faraji, A. H., Jaquins‐Gerstl, A., Valenta, A. C., Ou, Y., Richardson, R. M., & Weber, S. G. (2018) · Neurosurgery · doi:10.1093/neuros/nyy303.340 · Cited by 1 · see citing works
Carbohydrate Sulfotransferase 10 (CHST10)
Bakker, H. (2014) · Springer eBooks · doi:10.1007/978-4-431-54240-7_7
Santos, J. E. P. (2014) · doi:10.11606/t.17.2014.tde-19122014-154406
Perinodal ECM - its role in diffusion barrier formation and conduction velocity in the CNS
Bekku, Y., Ninomiya, Y., & Oohashi, T. (2012) · Okayama Igakkai Zasshi (Journal of Okayama Medical Association) · doi:10.4044/joma.124.1
Ivanov, S. M., Sukhachev, V. S., Tarasova, O. A., Lagunin, A. A., & Poroikov, V. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26199557
McKenna, M., Filteau, J. R., Butler, B., Sluis, K., Chungyoun, M., Schimek, N., & Nance, E. A. (2022) · Figshare · doi:10.6084/m9.figshare.20064215
- Authors
- Syková, E., Voříšek, I., Mazel, T., Antonova, T., & Schachner, M.
- Affiliations
- Czech Academy of Sciences (CZ)
- Universität Hamburg (DE)
- Venue
- European Journal of Neuroscience
- Publisher
- Wiley
- Published
- 2005-10
- Volume
- 22
- Issue
- 8
- Pages
- 1873-1880
- ISSN
- 0953-816X (ISSN-L)
- 1460-9568
- OpenAlex
- W2011868036
- Semantic Scholar
- 102d286c5240eea68a5877cde4c2aa98c63eb593
- Cited by
- 73
- References
- 50
- Citations by year
- 2026: 1 · 2025: 3 · 2023: 3 · 2022: 5 · 2021: 1 · 2020: 1 · 2019: 5 · 2018: 4 · 2017: 3 · 2016: 4 · 2015: 1 · 2014: 8 · 2013: 1 · 2012: 8
- FWCI
- 1.76
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- Funders
- Grantová Agentura České Republiky
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
- Keywords
- tenascin-R, tenascin-C, extracellular space, extracellular matrix, water diffusion, apparent diffusion coefficient, hippocampus, cerebral cortex, neuron-glia interactions
- MeSH terms
- Quaternary Ammonium Compounds, Animals, Brain, Extracellular Space, Female, Image Processing, Computer-Assisted, Iontophoresis, Mice, Inbred C57BL, Sulfotransferases, Mice, Knockout, Tenascin, Diffusion Magnetic Resonance Imaging, Mice
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