LAR inhibitory peptide promotes recovery of diaphragm function and multiple forms of respiratory neural circuit plasticity after cervical spinal cord injury.
LAR inhibitory peptide promotes recovery of diaphragm function and multiple forms of respiratory neural circuit plasticity after cervical spinal cord injury.
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DOI：
10.1016/j.nbd.2020.105153
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发表时间：
2021-01
影响因子：
6.1
通讯作者：
Lepore AC
中科院分区：
文献类型：
--
作者：
Cheng L;Sami A;Ghosh B;Urban MW;Heinsinger NM;Liang SS;Smith GM;Wright MC;Li S;Lepore AC
硫酸软骨素蛋白聚糖（CSPG）在创伤性脊髓损伤（SCI）后在损伤内和周围上调，是限制轴突生长和随后的功能恢复的关键细胞外基质抑制分子。CSPG介导的抑制通过与轴突受体（包括白细胞共同抗原相关（LAR）磷酸酶）的相互作用发生。我们测试了一种新的LAR抑制肽在大鼠颈2水平半切后的作用，这是一种SCI模型，其中起源于延髓头端腹侧呼吸组（rVRG）的球脊髓吸气神经回路与颈髓中的膈运动神经元（PhMN）靶点断开连接，导致持续的部分至完全膈肌麻痹。LAR肽通过浸泡的明胶海绵递送，明胶海绵在C2半切后立即直接放置在损伤部位上，并在损伤后1周更换。起源于同侧髓质的轴突切断的rVRG轴突或起源于对侧髓质的备用rVRG纤维通过经由AAV 2-mCherry注射到rVRG中的顺行追踪分别评估。在半切术后8周，LAR肽显著改善同侧半膈功能，如在体内用肌电图记录评估的。LAR肽促进同侧起源的rVRG轴突进入并通过病变部位并进入完整的尾脊髓以到达位于C3-C5水平的PhMN的稳健再生。此外，再生rVRG轴突重新建立假定的单突触连接与他们的PhMN的目标。此外，LAR肽刺激了PhMN池同侧/尾侧半切内的调节性轴突和对侧起源的rVRG纤维的稳健发芽。我们的研究表明，靶向基于LAR的轴突生长抑制促进多种形式的呼吸神经回路可塑性，并提供了一种新的基于肽的治疗策略，以改善SCI的破坏性呼吸后果。
Chondroitin sulfate proteoglycans (CSPGs), up-regulated in and around the lesion after traumatic spinal cord injury (SCI), are key extracellular matrix inhibitory molecules that limit axon growth and consequent recovery of function. CSPG-mediated inhibition occurs via interactions with axonal receptors, including leukocyte common antigen- related (LAR) phosphatase. We tested the effects of a novel LAR inhibitory peptide in rats after hemisection at cervical level 2, a SCI model in which bulbospinal inspiratory neural circuitry originating in the medullary rostral ventral respiratory group (rVRG) becomes disconnected from phrenic motor neuron (PhMN) targets in cervical spinal cord, resulting in persistent partial-to-complete diaphragm paralysis. LAR peptide was delivered by a soaked gelfoam, which was placed directly over the injury site immediately after C2 hemisection and replaced at 1 week post-injury. Axotomized rVRG axons originating in ipsilateral medulla or spared rVRG fibers originating in contralateral medulla were separately assessed by anterograde tracing via AAV2-mCherry injection into rVRG. At 8 weeks post-hemisection, LAR peptide significantly improved ipsilateral hemidiaphragm function, as assessed in vivo with electromyography recordings. LAR peptide promoted robust regeneration of ipsilateral-originating rVRG axons into and through the lesion site and into intact caudal spinal cord to reach PhMNs located at C3-C5 levels. Furthermore, regenerating rVRG axons re-established putative monosynaptic connections with their PhMNs targets. In addition, LAR peptide stimulated robust sprouting of both modulatory serotonergic axons and contralateral-originating rVRG fibers within the PhMN pool ipsilateral/ caudal to the hemisection. Our study demonstrates that targeting LAR-based axon growth inhibition promotes multiple forms of respiratory neural circuit plasticity and provides a new peptide-based therapeutic strategy to ameliorate the devastating respiratory consequences of SCI.
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影响因子：
9.3
作者：
Dyck S;Kataria H;Alizadeh A;Santhosh KT;Lang B;Silver J;Karimi-Abdolrezaee S
通讯作者：
Karimi-Abdolrezaee S
影响因子：
3
作者：
Franco, Santos J.;Mueller, Ulrich
通讯作者：
Mueller, Ulrich
影响因子：
16.2
作者：
Burda JE;Sofroniew MV
通讯作者：
Sofroniew MV
影响因子：
6.2
作者：
Dyck, Scott;Kataria, Hardeep;Karinni-Abdolrezaee, Soheila
通讯作者：
Karinni-Abdolrezaee, Soheila
影响因子：
5.2
作者：
Dale-Nagle EA;Hoffman MS;MacFarlane PM;Satriotomo I;Lovett-Barr MR;Vinit S;Mitchell GS
通讯作者：
Mitchell GS