A deficiency of the link protein Bral2 affects the size of the extracellular space in the thalamus of aged mice

J Neurosci Res. 2018 Feb;96(2):313-327. doi: 10.1002/jnr.24136. Epub 2017 Aug 16.


Bral2 is a link protein stabilizing the binding between lecticans and hyaluronan in perineuronal nets and axonal coats (ACs) in specific brain regions. Using the real-time iontophoretic method and diffusion-weighted magnetic resonance, we determined the extracellular space (ECS) volume fraction (α), tortuosity (λ), and apparent diffusion coefficient of water (ADCW ) in the thalamic ventral posteromedial nucleus (VPM) and sensorimotor cortex of young adult (3-6 months) and aged (14-20 months) Bral2-deficient (Bral2-/- ) mice and age-matched wild-type (wt) controls. The results were correlated with an analysis of extracellular matrix composition. In the cortex, no changes between wt and Bral2-/- were detected, either in the young or aged mice. In the VPM of aged but not in young Bral2-/- mice, we observed a significant decrease in α and ADCW in comparison with age-matched controls. Bral2 deficiency led to a reduction of both aggrecan- and brevican-associated perineuronal nets and a complete disruption of brevican-based ACs in young as well as aged VPM. Our data suggest that aging is a critical point that reveals the effect of Bral2 deficiency on VPM diffusion. This effect is probably mediated through the enhanced age-related damage of neurons lacking protective ACs, or the exhausting of compensatory mechanisms maintaining unchanged diffusion parameters in young Bral2-/- animals. A decreased ECS volume in aged Bral2-/- mice may influence the diffusion of neuroactive substances, and thus extrasynaptic and also indirectly synaptic transmission in this important nucleus of the somatosensory pathway.

Keywords: Bral2; aging; diffusion; extracellular matrix; extracellular space.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aggrecans / metabolism
  • Aging / physiology*
  • Analysis of Variance
  • Animals
  • Animals, Newborn
  • Diffusion Magnetic Resonance Imaging
  • Extracellular Matrix Proteins / deficiency*
  • Extracellular Matrix Proteins / genetics
  • Extracellular Space / diagnostic imaging
  • Extracellular Space / genetics*
  • Female
  • Ganglionic Stimulants / pharmacology
  • In Vitro Techniques
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nerve Tissue Proteins / deficiency*
  • Nerve Tissue Proteins / genetics
  • Neurons / cytology*
  • Neurons / drug effects
  • Quaternary Ammonium Compounds / pharmacology
  • RNA, Messenger
  • Thalamus / cytology*


  • Aggrecans
  • Extracellular Matrix Proteins
  • Ganglionic Stimulants
  • Hapln4 protein, mouse
  • Nerve Tissue Proteins
  • Quaternary Ammonium Compounds
  • RNA, Messenger
  • tetramethylammonium