Oral treatment of 4-methylumbelliferone reduced perineuronal nets and improved recognition memory in mice.
Oral treatment of 4-methylumbelliferone reduced perineuronal nets and improved recognition memory in mice.
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DOI：
10.1016/j.brainresbull.2022.01.011
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发表时间：
2022-04
影响因子：
3.8
通讯作者：
Kubinova S
中科院分区：
文献类型：
--
作者：
Dubisova J;Burianova JS;Svobodova L;Makovicky P;Martinez-Varea N;Cimpean A;Fawcett JW;Kwok JCF;Kubinova S
透明质酸（HA）是神经元周围神经元网络（PNN）的核心组成部分。PNNs控制发育中和成年中枢神经系统中的突触稳定性，并且PNNs的破坏已显示出重新激活神经可塑性。我们研究了使用HA合成抑制剂4-甲基伞形酮（4-MU）通过衰减PNN形成来延长记忆的可能性。成年C57 BL/6小鼠以约6.7 mg/g/天的剂量喂食含有5%（w/w）4-MU的食物6个月。与对照组相比，4-MU的口服给药使脑中的糖胺聚糖水平降低至72%，脊髓中的糖胺聚糖水平降低至50%。在2、3、6和7个月时进行的自发物体识别测试（SOR）显示，在物体呈现后24小时，6个月治疗组的SOR评分显著增加。然而，该效应在洗脱组中不持续（治疗后1个月）。免疫组织化学证实PNN减少，4-MU治疗6个月后海马树突周围聚集蛋白聚糖染色的树枝状变短且变少。组织学检查显示关节软骨轻度萎缩，但不影响旋转棒试验所示的运动性能。总之，全身口服4-MU 6个月减少了神经元周围PNN的形成，增强了小鼠的记忆力。然而，尽管PNN减少，但记忆增强并不持续，可能是由于在洗脱期缺乏记忆增强训练。我们的结果表明，4-MU治疗可能提供了PNN调节记忆增强的策略。去除神经元周围网（PNNs）可以重新激活神经可塑性。口服4-甲基伞形酮（4-MU）可减少PNN。PNN减少导致小鼠识别记忆增强。记忆效果不持久可能是由于缺乏记忆训练。
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. Removal of perineuronal nets (PNNs) reactivates neuroplasticity. Oral administration of 4-methylumbelliferone (4-MU) reduces PNNs. PNN reduction leads to enhancement in recognition memory in mice. The memory effect is not sustained likely due to a lack of memory training.
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影响因子：
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作者：
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作者：
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DOI：
10.1073/pnas.1525086113
发表时间：
2016-02-02
影响因子：
11.1
作者：
Kuipers, Hedwich F.;Rieck, Mary;Bollyky, Paul L.
通讯作者：
Bollyky, Paul L.