Groemer Teja Wolfgang, Triller Antoine, Zeilhofer Hanns Ulrich, Becker Kristina, Eulenburg Volker, Becker Cord Michael
Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
École Normale Supérieure, INSERM U 497 Biologie Cellulaire de la Synapse Normale et Pathologique, Paris, France.
Front Mol Neurosci. 2022 Apr 25;15:832490. doi: 10.3389/fnmol.2022.832490. eCollection 2022.
Glycine receptors (GlyRs) are the primary mediators of fast inhibitory transmission in the mammalian spinal cord, where they modulate sensory and motor signaling. Mutations in GlyR genes as well as some other genes underlie the hereditary disorder hyperekplexia, characterized by episodic muscle stiffness and exaggerated startle responses. Here, we have investigated pain-related behavior and GlyR expression in the spinal cord of the GlyR deficient mutant mouse (). In mice, the GlyR number is reduced due to a β subunit gene () mutation resulting in aberrant splicing of GlyRβ transcripts. direct physical interaction with the GlyR anchoring protein gephyrin, this subunit is crucially involved in the postsynaptic clustering of heteromeric GlyRs. We show that the mutation differentially affects aspects of the pain-related behavior of homozygous Glrb/Glrb mice. While response latencies to noxious heat were unchanged, chemically induced pain-related behavior revealed a reduction of the licking time and an increase in flinching in spastic homozygotes during both phases of the formalin test. Mechanically induced nocifensive behavior was reduced in spastic mice, although hind paw inflammation (by zymosan) resulted in allodynia comparable to wild-type mice. Immunohistochemical staining of the spinal cord revealed a massive reduction of dotted GlyRα subunit immunoreactivity in both ventral and dorsal horns, suggesting a reduction of clustered receptors at synaptic sites. Transcripts for all GlyRα subunit variants, however, were not reduced throughout the dorsal horn of mice. These findings suggest that the loss of functional GlyRβ subunits and hence synaptically localized GlyRs compromises sensory processing differentially, depending on stimulus modality.
甘氨酸受体（GlyRs）是哺乳动物脊髓中快速抑制性传递的主要介质，在脊髓中调节感觉和运动信号。GlyR基因以及其他一些基因的突变是遗传性疾病惊吓症的基础，其特征为发作性肌肉僵硬和夸张的惊吓反应。在此，我们研究了GlyR缺陷型突变小鼠脊髓中与疼痛相关的行为和GlyR表达。在该小鼠中，由于β亚基基因（）突变导致GlyRβ转录本异常剪接，GlyR数量减少。该亚基通过与GlyR锚定蛋白gephyrin直接物理相互作用，在异聚体GlyRs的突触后聚集过程中起关键作用。我们发现该突变对纯合Glrb/Glrb小鼠与疼痛相关行为的各个方面有不同影响。虽然对有害热刺激的反应潜伏期未变，但化学诱导的与疼痛相关行为显示，在福尔马林试验的两个阶段，痉挛性纯合子的舔舐时间减少，退缩增加。痉挛性小鼠的机械诱导伤害防御行为减少，尽管酵母聚糖诱导的后爪炎症导致与野生型小鼠相当的异常性疼痛。脊髓的免疫组织化学染色显示，腹角和背角中点状GlyRα亚基免疫反应性均大幅降低，表明突触部位聚集的受体减少。然而，在该小鼠的整个背角中，所有GlyRα亚基变体的转录本并未减少。这些发现表明，功能性GlyRβ亚基的缺失以及因此突触定位的GlyRs的缺失，根据刺激方式的不同，对感觉处理产生不同程度的损害。
