Schneider Erich H, Fowler Stephen C, Lionakis Michail S, Swamydas Muthulekha, Holmes Gibran, Diaz Vivian, Munasinghe Jeeva, Peiper Stephen C, Gao Ji-Liang, Murphy Philip M
Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases (NIAID)/NIH, Bethesda, MD, USA.
Behav Genet. 2014 Sep;44(5):498-515. doi: 10.1007/s10519-014-9665-7. Epub 2014 Jul 6.
Atypical Chemokine Receptor 1 (ACKR1), previously known as Duffy Antigen Receptor for Chemokines, stands out among chemokine receptors for high selective expression on cerebellar Purkinje neurons. Although ACKR1 ligands activate Purkinje cells in vitro, evidence for ACKR1 regulation of brain function in vivo is lacking. Here we demonstrate that Ackr1 (-/-) mice have markedly impaired balance and ataxia on a rotating rod and increased tremor when injected with harmaline, which induces whole-body tremor by activating Purkinje cells. Ackr1 (-/-) mice also exhibited impaired exploratory behavior, increased anxiety-like behavior and frequent episodes of marked hypoactivity under low-stress conditions. Surprisingly, Ackr1 (+/-) had similar behavioral abnormalities, indicating pronounced haploinsufficiency. The behavioral phenotype of Ackr1 (-/-) mice was the opposite of mouse models of cerebellar degeneration, and the defects persisted when Ackr1 was deficient only on non-hematopoietic cells. Together, the results suggest that normal motor function and behavior may partly depend on negative regulation of Purkinje cell activity by Ackr1.
非典型趋化因子受体1（ACKR1），以前称为趋化因子的达菲抗原受体，在趋化因子受体中脱颖而出，因为它在小脑浦肯野神经元上有高度选择性表达。尽管ACKR1配体在体外可激活浦肯野细胞，但缺乏ACKR1在体内调节脑功能的证据。在此我们证明，Ackr1基因敲除小鼠在转棒试验中平衡能力显著受损且共济失调，注射 harmaline（通过激活浦肯野细胞诱导全身震颤）后震颤增加。Ackr1基因敲除小鼠在低应激条件下还表现出探索行为受损、焦虑样行为增加以及频繁出现明显的活动减退。令人惊讶的是，Ackr1杂合子小鼠也有类似的行为异常，表明存在明显的单倍剂量不足。Ackr1基因敲除小鼠的行为表型与小脑变性小鼠模型相反，并且当Ackr1仅在非造血细胞中缺乏时，这些缺陷仍然存在。总之，结果表明正常的运动功能和行为可能部分依赖于Ackr1对浦肯野细胞活性的负调节。
