Ricardo Martín, Alberto Samuel Suárez-Pinilla, Nuria García-Font, M Luisa Laguna-Luque, Juan C López-Ramos, María Jesús Oset-Gasque, Agnes Gruart, José M Delgado-García, Magdalena Torres, José Sánchez-Prieto
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FXS patients and mice lacking FMRP suffer from multiple behavioral alterations, including deficits in motor learning for which there is currently no specific treatment.</p><p><strong>Methods: </strong>We performed electron microscopy, whole-cell patch-clamp electrophysiology and behavioral experiments to characterise the synaptic mechanisms underlying the motor learning deficits observed in Fmr1KO mice and the therapeutic potential of positive allosteric modulator of mGluR4.</p><p><strong>Results: </strong>We found that enhanced synaptic vesicle docking of cerebellar parallel fiber to Purkinje cell Fmr1KO synapses was associated with enhanced asynchronous release, which not only prevents further potentiation, but it also compromises presynaptic parallel fiber long-term potentiation (PF-LTP) mediated by β adrenergic receptors. A reduction in extracellular Ca<sup>2+</sup> concentration restored the readily releasable pool (RRP) size, basal synaptic transmission, β adrenergic receptor-mediated potentiation, and PF-LTP. Interestingly, VU 0155041, a selective positive allosteric modulator of mGluR4, also restored both the RRP size and PF-LTP in mice of either sex. Moreover, when injected into Fmr1KO male mice, VU 0155041 improved motor learning in skilled reaching, classical eyeblink conditioning and vestibuloocular reflex (VOR) tests, as well as the social behavior alterations of these mice.</p><p><strong>Limitations: </strong>We cannot rule out that the activation of mGluR4s via systemic administration of VU0155041 can also affect other brain regions. Further studies are needed to stablish the effect of a specific activation of mGluR4 in cerebellar granule cells.</p><p><strong>Conclusions: </strong>Our study shows that an increase in synaptic vesicles, SV, docking may cause the loss of PF-LTP and motor learning and social deficits of Fmr1KO mice and that the reversal of these changes by pharmacological activation of mGluR4 may offer therapeutic relief for motor learning and social deficits in FXS.</p>","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":"14 1","pages":"14"},"PeriodicalIF":6.3000,"publicationDate":"2023-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10082511/pdf/","citationCount":"0","resultStr":"{\"title\":\"The activation of mGluR4 rescues parallel fiber synaptic transmission and LTP, motor learning and social behavior in a mouse model of Fragile X Syndrome.\",\"authors\":\"Ricardo Martín, Alberto Samuel Suárez-Pinilla, Nuria García-Font, M Luisa Laguna-Luque, Juan C López-Ramos, María Jesús Oset-Gasque, Agnes Gruart, José M Delgado-García, Magdalena Torres, José Sánchez-Prieto\",\"doi\":\"10.1186/s13229-023-00547-4\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Fragile X syndrome (FXS), the most common inherited intellectual disability, is caused by the loss of expression of the Fragile X Messenger Ribonucleoprotein (FMRP). FMRP is an RNA-binding protein that negatively regulates the expression of many postsynaptic as well as presynaptic proteins involved in action potential properties, calcium homeostasis and neurotransmitter release. FXS patients and mice lacking FMRP suffer from multiple behavioral alterations, including deficits in motor learning for which there is currently no specific treatment.</p><p><strong>Methods: </strong>We performed electron microscopy, whole-cell patch-clamp electrophysiology and behavioral experiments to characterise the synaptic mechanisms underlying the motor learning deficits observed in Fmr1KO mice and the therapeutic potential of positive allosteric modulator of mGluR4.</p><p><strong>Results: </strong>We found that enhanced synaptic vesicle docking of cerebellar parallel fiber to Purkinje cell Fmr1KO synapses was associated with enhanced asynchronous release, which not only prevents further potentiation, but it also compromises presynaptic parallel fiber long-term potentiation (PF-LTP) mediated by β adrenergic receptors. A reduction in extracellular Ca<sup>2+</sup> concentration restored the readily releasable pool (RRP) size, basal synaptic transmission, β adrenergic receptor-mediated potentiation, and PF-LTP. Interestingly, VU 0155041, a selective positive allosteric modulator of mGluR4, also restored both the RRP size and PF-LTP in mice of either sex. Moreover, when injected into Fmr1KO male mice, VU 0155041 improved motor learning in skilled reaching, classical eyeblink conditioning and vestibuloocular reflex (VOR) tests, as well as the social behavior alterations of these mice.</p><p><strong>Limitations: </strong>We cannot rule out that the activation of mGluR4s via systemic administration of VU0155041 can also affect other brain regions. 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引用次数: 0
摘要
背景:脆性X综合征(Fragile X syndrome, FXS)是最常见的遗传性智力残疾,由脆性X信使核糖核蛋白(Fragile X Messenger ribonnucleoprotein, FMRP)表达缺失引起。FMRP是一种rna结合蛋白,可负性调节许多突触后和突触前蛋白的表达,这些蛋白参与动作电位特性、钙稳态和神经递质释放。FXS患者和缺乏FMRP的小鼠会出现多种行为改变,包括运动学习缺陷,目前尚无具体治疗方法。方法:我们通过电镜、全细胞膜片钳电生理和行为实验来表征Fmr1KO小鼠运动学习缺陷的突触机制,以及mGluR4阳性变构调节剂的治疗潜力。结果:我们发现小脑平行纤维与浦肯野细胞Fmr1KO突触突触囊泡对接增强与异步释放增强相关,这不仅阻止了进一步的增强,而且还破坏了β肾上腺素能受体介导的突触前平行纤维长期增强(PF-LTP)。细胞外Ca2+浓度的降低恢复了易释放池(RRP)大小、基础突触传递、β肾上腺素能受体介导的增强和PF-LTP。有趣的是,mGluR4的选择性阳性变构调节剂VU 0155041也能恢复小鼠的RRP大小和PF-LTP。此外,当注射到Fmr1KO雄性小鼠时,VU 0155041改善了这些小鼠在熟练伸臂、经典眨眼条件反射和前庭反射(VOR)测试中的运动学习,以及社会行为的改变。局限性:我们不能排除通过系统给药VU0155041激活mGluR4s也可以影响其他大脑区域。需要进一步的研究来确定mGluR4在小脑颗粒细胞中的特异性激活作用。结论:我们的研究表明,突触囊泡、SV、对接的增加可能导致Fmr1KO小鼠PF-LTP的缺失以及运动学习和社交缺陷,通过药物激活mGluR4逆转这些变化可能对FXS的运动学习和社交缺陷提供治疗性缓解。
The activation of mGluR4 rescues parallel fiber synaptic transmission and LTP, motor learning and social behavior in a mouse model of Fragile X Syndrome.
Background: Fragile X syndrome (FXS), the most common inherited intellectual disability, is caused by the loss of expression of the Fragile X Messenger Ribonucleoprotein (FMRP). FMRP is an RNA-binding protein that negatively regulates the expression of many postsynaptic as well as presynaptic proteins involved in action potential properties, calcium homeostasis and neurotransmitter release. FXS patients and mice lacking FMRP suffer from multiple behavioral alterations, including deficits in motor learning for which there is currently no specific treatment.
Methods: We performed electron microscopy, whole-cell patch-clamp electrophysiology and behavioral experiments to characterise the synaptic mechanisms underlying the motor learning deficits observed in Fmr1KO mice and the therapeutic potential of positive allosteric modulator of mGluR4.
Results: We found that enhanced synaptic vesicle docking of cerebellar parallel fiber to Purkinje cell Fmr1KO synapses was associated with enhanced asynchronous release, which not only prevents further potentiation, but it also compromises presynaptic parallel fiber long-term potentiation (PF-LTP) mediated by β adrenergic receptors. A reduction in extracellular Ca2+ concentration restored the readily releasable pool (RRP) size, basal synaptic transmission, β adrenergic receptor-mediated potentiation, and PF-LTP. Interestingly, VU 0155041, a selective positive allosteric modulator of mGluR4, also restored both the RRP size and PF-LTP in mice of either sex. Moreover, when injected into Fmr1KO male mice, VU 0155041 improved motor learning in skilled reaching, classical eyeblink conditioning and vestibuloocular reflex (VOR) tests, as well as the social behavior alterations of these mice.
Limitations: We cannot rule out that the activation of mGluR4s via systemic administration of VU0155041 can also affect other brain regions. Further studies are needed to stablish the effect of a specific activation of mGluR4 in cerebellar granule cells.
Conclusions: Our study shows that an increase in synaptic vesicles, SV, docking may cause the loss of PF-LTP and motor learning and social deficits of Fmr1KO mice and that the reversal of these changes by pharmacological activation of mGluR4 may offer therapeutic relief for motor learning and social deficits in FXS.
期刊介绍:
Molecular Autism is a peer-reviewed, open access journal that publishes high-quality basic, translational and clinical research that has relevance to the etiology, pathobiology, or treatment of autism and related neurodevelopmental conditions. Research that includes integration across levels is encouraged. Molecular Autism publishes empirical studies, reviews, and brief communications.