Restless legs syndrome (RLS) is a nocturnal neurological disorder affecting up to 10% of the population. It is characterized by an urge to move and uncomfortable sensations in the legs which can be relieved by movements. Mutations in BTBD9 may confer a higher risk of RLS. We developed Btbd9 knockout mice as an animal model. Functional alterations in the cerebral cortex, especially the sensorimotor cortex, have been found in RLS patients in several imaging studies. However, the role of cerebral cortex in the pathogenesis of RLS remains unclear. To explore this, we used in vivo manganese-enhanced MRI and found that the Btbd9 knockout mice had significantly increased neural activities in the primary somatosensory cortex (S1) and the rostral piriform cortex. Morphometry study revealed a decreased thickness in a part of S1 representing the hindlimb (S1HL) and M1. The electrophysiological recording showed Btbd9 knockout mice had enhanced short-term plasticity at the corticostriatal terminals to D1 medium spiny neurons (MSNs). Furthermore, we specifically knocked out Btbd9 in the cerebral cortex of mice (Btbd9 cKO). The Btbd9 cKO mice showed a rest-phase specific motor restlessness, decreased thermal sensation, and a thinner S1HL and M1. Both Btbd9 knockout and Btbd9 cKO exhibited motor deficits. Our results indicate that systematic BTBD9 deficiency leads to both functional and morphometrical changes of the cerebral cortex, and an alteration in the corticostriatal pathway to D1 MSNs. Loss of BTBD9 only in the cerebral cortex is sufficient to cause similar phenotypes as observed in the Btbd9 complete knockout mice.

不安腿综合征（RLS）是一种夜间神经系统疾病，可影响多达10％的人口。它的特点是强烈的运动欲望和腿部不适感，可通过运动缓解。BTBD9中的突变可能赋予RLS更高的风险。我们开发了Btbd9基因敲除小鼠作为动物模型。在几项影像学研究中，已在RLS患者中发现了大脑皮层，特别是感觉运动皮层的功能改变。然而，大脑皮层在RLS发病机理中的作用尚不清楚。为了探索这一点，我们使用了体内锰增强的MRI，发现Btbd9剔除小鼠的初级体感皮层（S1）和喙形梨状皮层的神经活动明显增加。形态计量学研究表明，代表后肢（S1HL）和M1的S1部分的厚度减小。电生理记录显示，Btbd9基因敲除小鼠的皮质口端对D1中等多刺神经元（MSNs）具有增强的短期可塑性。此外，我们专门敲除了小鼠大脑皮层中的Btbd9 （Btbd9 cKO）。所述BTBD9 CKO小鼠显示静止时相特异性马达躁动，减小的热感，和较薄S1HL和M1。无论BTBD9敲除和BTBD9cKO表现出运动缺陷。我们的结果表明，系统性BTBD9缺乏会导致大脑皮层的功能和形态变化，以及通往D1 MSNs的皮质口途径的改变。仅在大脑皮层中BTBD9的丧失足以引起与Btbd9完全敲除小鼠相似的表型。