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.
- MeSH
- agrekany metabolismus MeSH
- analýza rozptylu MeSH
- difuzní magnetická rezonance MeSH
- extracelulární matrix - proteiny nedostatek genetika MeSH
- extracelulární prostor diagnostické zobrazování genetika MeSH
- gangliová stimulancia farmakologie MeSH
- kvartérní amoniové sloučeniny farmakologie MeSH
- messenger RNA MeSH
- myši inbrední C57BL MeSH
- myši transgenní MeSH
- myši MeSH
- neurony cytologie účinky léků MeSH
- novorozená zvířata MeSH
- proteiny nervové tkáně nedostatek genetika MeSH
- stárnutí fyziologie MeSH
- techniky in vitro MeSH
- thalamus cytologie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. In a recent study by Steinberg and colleagues, 2 recessive missense mutations were identified in the Cav3.2 T-type calcium channel gene (CACNA1H), in a family with an affected proband (early onset, long duration ALS) and 2 unaffected parents. We have introduced and functionally characterized these mutations using transiently expressed human Cav3.2 channels in tsA-201 cells. Both of these mutations produced mild but significant changes on T-type channel activity that are consistent with a loss of channel function. Computer modeling in thalamic reticular neurons suggested that these mutations result in decreased neuronal excitability of thalamic structures. Taken together, these findings implicate CACNA1H as a susceptibility gene in amyotrophic lateral sclerosis.
- MeSH
- amyotrofická laterální skleróza genetika metabolismus patofyziologie MeSH
- buněčné linie MeSH
- lidé MeSH
- missense mutace * MeSH
- neurony fyziologie MeSH
- thalamus cytologie fyziologie MeSH
- transfekce MeSH
- vápníkové kanály - typ T genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
The responses of primate spinothalamic tract (STT) neurons to innocuous and noxious mechanical stimuli applied to the skin can be enhanced for more than an hour following prolonged noxious stimulation. This increased responsiveness is thought to reflect sensitization of dorsal horn neurons and may help account for secondary hyperalgesia and mechanical allodynia. The proposal that central sensitization is due to the activation of second messenger system was tested in this study by examining the effect of trans-ACPD (trans-D,L-1-amino-1,3-cyclopentanedicarboxylic acid), an agonist of metabotropic excitatory amino acid (EAA) receptors, introduced into the dorsal horn by microdialysis. A low dose of trans-ACPD resulted in an increase in the responses of STT cells to an innocuous mechanical stimulus (BRUSH), but no increase in the responses to noxious mechanical and thermal stimuli or in the excitation produced by iontophoretically applied EAAs. A high dose of trans-ACPD caused a transient increase in background activity, but no change in the responsiveness of spinothalamic cells to any of the test stimuli. It is concluded that low doses of trans-ACPD can selectively enhance transmission through interneuronal pathways mediating tactile inputs to spinothalamic cells.
- MeSH
- akční potenciály účinky léků MeSH
- aminokyseliny farmakologie MeSH
- cykloleucin analogy a deriváty aplikace a dávkování farmakologie MeSH
- fyzikální stimulace MeSH
- Macaca fascicularis MeSH
- mícha * cytologie účinky léků MeSH
- mikrodialýza MeSH
- nervové dráhy cytologie účinky léků MeSH
- neurony * účinky léků MeSH
- neurotoxiny aplikace a dávkování farmakologie MeSH
- receptory metabotropního glutamátu * účinky léků MeSH
- thalamus * cytologie účinky léků MeSH
- vysoká teplota MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, P.H.S. MeSH
