MacDermid V E, McPhail L T, Tsang B, Rosenthal A, Davies A, Ramer M S
International Collaboration on Repair Discoveries, University of British Columbia, 2469-6270 University Blvd, Vancouver, British Columbia, Canada V6T 1Z4.
Eur J Neurosci. 2004 Nov;20(10):2567-79. doi: 10.1111/j.1460-9568.2004.03715.x.
In the central nervous system, regeneration of injured axons and sprouting of intact axons are suppressed by myelin-derived molecules that bind to the Nogo receptor (NgR). We used a soluble form of the NgR (sNgR), constructed as an IgG of the human NgR extracellular domain, to manipulate plasticity of uninjured primary afferent and descending monoaminergic projections to the rat spinal cord following dorsal rhizotomy. Rats with quadruple dorsal rhizotomies were treated with intrathecal sNgR or saline, or were left untreated for 2 weeks. Rhizotomy alone resulted in sprouting of serotonergic axons and to a lesser extent, tyrosine-hydroxylase (TH)-expressing axons, while axons expressing dopamine-beta-hydroxylase (DbetaH) were unaffected. Human IgG immunohistochemistry revealed that sNgR infused into the intrathecal space penetrated approximately 300 microm into spinal white and grey matter. Separate axonal populations differed in their responses to intrathecal sNgR: TH-expressing and DbetaH-expressing axons responded most and least vigorously, respectively. Serotonergic axons were identified by serotonin (5-HT) or serotonin transporter (SERT) immunohistochemistry. Interestingly, a large increase in 5-HT compared to SERT-positive axons density in both saline and sNgR-treated rats indicated that serotonergic axons both sprouted and increased their transmitter content in response to rhizotomy and sNgR treatment. Calcitonin gene-related peptide-positive axons were largely depleted ipsilaterally by rhizotomy, and sNgR increased axon density only in deeper contralateral laminae (III-V). GAP-43 immunohistochemistry revealed a small increase in axon density following dorsal rhizotomy that was further augmented by sNgR treatment. These results reveal a differential effect of myelin antagonism on distinct populations of spinally projecting axons.
在中枢神经系统中，与Nogo受体（NgR）结合的髓磷脂衍生分子会抑制受损轴突的再生和完整轴突的出芽。我们使用了一种可溶性形式的NgR（sNgR），它被构建为人NgR细胞外结构域的IgG，以操控在大鼠背根切断术后未受损的初级传入和下行单胺能投射至脊髓的可塑性。对进行了四次背根切断术的大鼠进行鞘内注射sNgR或生理盐水治疗，或不进行治疗，持续2周。仅背根切断术就导致了5-羟色胺能轴突发芽，酪氨酸羟化酶（TH）表达的轴突在较小程度上出芽，而表达多巴胺-β-羟化酶（DβH）的轴突则未受影响。人IgG免疫组织化学显示，注入鞘内空间的sNgR可穿透约300微米进入脊髓白质和灰质。不同的轴突群体对鞘内sNgR的反应不同：表达TH的轴突反应最强烈，表达DβH的轴突反应最不强烈。5-羟色胺能轴突通过5-羟色胺（5-HT）或5-羟色胺转运体（SERT）免疫组织化学进行鉴定。有趣的是，在生理盐水和sNgR治疗的大鼠中，5-HT与SERT阳性轴突密度相比大幅增加，这表明5-羟色胺能轴突在背根切断术和sNgR治疗后既出芽又增加了其递质含量。降钙素基因相关肽阳性轴突在同侧大部分被背根切断术耗尽，而sNgR仅增加了对侧更深层板层（III-V）的轴突密度。GAP-43免疫组织化学显示，背根切断术后轴突密度有小幅增加，而sNgR治疗进一步增强了这种增加。这些结果揭示了髓磷脂拮抗作用对不同脊髓投射轴突群体的不同影响。
