Hyaluronan (HA) is a core constituent of perineuronal nets (PNNs) that surround subpopulations of neurones. The PNNs control synaptic stabilization in both the developing and adult central nervous system, and disruption of PNNs has shown to reactivate neuroplasticity. We investigated the possibility of memory prolongation by attenuating PNN formation using 4-methylumbelliferone (4-MU), an inhibitor of HA synthesis. Adult C57BL/6 mice were fed with chow containing 5% (w/w) 4-MU for 6 months, at a dose ~6.7 mg/g/day. The oral administration of 4-MU reduced the glycosaminoglycan level in the brain to 72% and the spinal cord to 50% when compared to the controls. Spontaneous object recognition test (SOR) performed at 2, 3, 6 and 7 months showed a significant increase in SOR score in the 6-months treatment group 24 h after object presentation. The effect however did not persist in the washout group (1-month post treatment). Immunohistochemistry confirmed a reduction of PNNs, with shorter and less arborization of aggrecan staining around dendrites in hippocampus after 6 months of 4-MU treatment. Histopathological examination revealed mild atrophy in articular cartilage but it did not affect the motor performance as demonstrated in rotarod test. In conclusion, systemic oral administration of 4-MU for 6 months reduced PNN formation around neurons and enhanced memory retention in mice. However, the memory enhancement was not sustained despite the reduction of PNNs, possibly due to the lack of memory enhancement training during the washout period. Our results suggest that 4-MU treatment might offer a strategy for PNN modulation in memory enhancement.
- MeSH
- agrekany účinky léků MeSH
- aplikace orální MeSH
- centrální nervový systém účinky léků MeSH
- chování zvířat účinky léků MeSH
- extracelulární matrix účinky léků MeSH
- hymekromon aplikace a dávkování farmakologie MeSH
- kyselina hyaluronová metabolismus MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- neuroplasticita účinky léků MeSH
- oligodendroglie účinky léků MeSH
- rozpoznávání (psychologie) účinky léků MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
In the adult brain, the extracellular matrix (ECM) influences recovery after injury, susceptibility to mental disorders, and is in general a strong regulator of neuronal plasticity. The proteoglycan aggrecan is a core component of the condensed ECM structures termed perineuronal nets (PNNs), and the specific role of PNNs on neural plasticity remains elusive. Here, we genetically targeted the Acan gene encoding for aggrecan using a novel animal model. This allowed for conditional and targeted loss of aggrecan in vivo, which ablated the PNN structure and caused a shift in the population of parvalbumin-expressing inhibitory interneurons toward a high plasticity state. Selective deletion of the Acan gene in the visual cortex of male adult mice reinstated juvenile ocular dominance plasticity, which was mechanistically identical to critical period plasticity. Brain-wide targeting improved object recognition memory.SIGNIFICANCE STATEMENT The study provides the first direct evidence of aggrecan as the main functional constituent and orchestrator of perineuronal nets (PNNs), and that loss of PNNs by aggrecan removal induces a permanent state of critical period-like plasticity. Loss of aggrecan ablates the PNN structure, resulting in invoked juvenile plasticity in the visual cortex and enhanced object recognition memory.
- MeSH
- agrekany analýza nedostatek genetika MeSH
- buněčné linie MeSH
- extracelulární matrix chemie genetika metabolismus MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- myši transgenní MeSH
- myši MeSH
- nervová síť chemie metabolismus MeSH
- neuroplasticita fyziologie MeSH
- světelná stimulace metody MeSH
- zrakové korové centrum chemie metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
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
Context: Heterozygous mutations in the aggrecan gene (ACAN) cause autosomal dominant short stature with accelerated skeletal maturation. Objective: We sought to characterize the phenotypic spectrum and response to growth-promoting therapies. Patients and Methods: One hundred three individuals (57 females, 46 males) from 20 families with autosomal dominant short stature and heterozygous ACAN mutations were identified and confirmed using whole-exome sequencing, targeted next-generation sequencing, and/or Sanger sequencing. Clinical information was collected from the medical records. Results: Identified ACAN variants showed perfect cosegregation with phenotype. Adult individuals had mildly disproportionate short stature [median height, -2.8 standard deviation score (SDS); range, -5.9 to -0.9] and a history of early growth cessation. The condition was frequently associated with early-onset osteoarthritis (12 families) and intervertebral disc disease (9 families). No apparent genotype-phenotype correlation was found between the type of ACAN mutation and the presence of joint complaints. Childhood height was less affected (median height, -2.0 SDS; range, -4.2 to -0.6). Most children with ACAN mutations had advanced bone age (bone age - chronologic age; median, +1.3 years; range, +0.0 to +3.7 years). Nineteen individuals had received growth hormone therapy with some evidence of increased growth velocity. Conclusions: Heterozygous ACAN mutations result in a phenotypic spectrum ranging from mild and proportionate short stature to a mild skeletal dysplasia with disproportionate short stature and brachydactyly. Many affected individuals developed early-onset osteoarthritis and degenerative disc disease, suggesting dysfunction of the articular cartilage and intervertebral disc cartilage. Additional studies are needed to determine the optimal treatment strategy for these patients.
- MeSH
- agrekany genetika MeSH
- antropometrie metody MeSH
- brachydaktylie genetika MeSH
- degenerace meziobratlové ploténky genetika MeSH
- dítě MeSH
- dospělí MeSH
- fenotyp MeSH
- heterozygot MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mutace * MeSH
- mutační analýza DNA metody MeSH
- nanismus farmakoterapie genetika MeSH
- osteochondritis dissecans vrozené genetika MeSH
- předškolní dítě MeSH
- rodokmen MeSH
- růst genetika MeSH
- růstový hormon terapeutické užití MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- výhřez meziobratlové ploténky genetika MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
Článek přináší přehled informací současného vědění o dění na osteochondrálním kloubním spoji za fyziologických i patologických stavů.
The article brings an overview of information concerning current knowledge about events on the articular osteochondral junction during physiological and pathological conditions.
- MeSH
- agrekany fyziologie MeSH
- chondrocyty MeSH
- extracelulární matrix fyziologie MeSH
- fibrilární kolageny MeSH
- hyalinní chrupavka MeSH
- kloubní chrupavka * patofyziologie MeSH
- kosti a kostní tkáň fyziologie patologie MeSH
- lidé MeSH
- nemoci chrupavky * patofyziologie MeSH
- osteoartróza * patofyziologie MeSH
- Check Tag
- lidé MeSH
ACI is the most widely used cell-based surgical procedure for the repair of articular cartilage defects. The method is based on in vitro chondrocyte cultivation. Two different culture conditions, rotating- wall-vessel bioreactor and static culture, were assessed by their effect on the re-differentiation potential of human articular chondrocytes seeded into a hydrogel scaffold. Gene expression analysis of the tissue-engineered construct revealed no significant difference between the tested systems.
- MeSH
- agrekany metabolismus MeSH
- bioreaktory MeSH
- buněčná diferenciace genetika MeSH
- buněčné kultury MeSH
- chondrocyty cytologie metabolismus transplantace MeSH
- exprese genu MeSH
- kloubní chrupavka cytologie metabolismus MeSH
- kolagen typ II metabolismus MeSH
- kolagen typu I metabolismus MeSH
- kultivované buňky MeSH
- lidé MeSH
- PEG-DMA hydrogel MeSH
- tkáňové inženýrství metody MeSH
- tkáňové podpůrné struktury MeSH
- versikany metabolismus MeSH
- Check Tag
- lidé MeSH
