Ribeiro Svethna, Sherrard Rachel M
UMR 8256 Biological Adaptation and Ageing, Sorbonne Université and CNRS, IBPS-B2A, Paris, France.
Front Cell Neurosci. 2023 Mar 30;17:1108339. doi: 10.3389/fncel.2023.1108339. eCollection 2023.
Errors of cerebellar development are increasingly acknowledged as risk factors for neuro-developmental disorders (NDDs), such as attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and schizophrenia. Evidence has been assembled from cerebellar abnormalities in autistic patients, as well as a range of genetic mutations identified in human patients that affect the cerebellar circuit, particularly Purkinje cells, and are associated with deficits of motor function, learning and social behavior; traits that are commonly associated with autism and schizophrenia. However, NDDs, such as ASD and schizophrenia, also include systemic abnormalities, e.g., chronic inflammation, abnormal circadian rhythms etc., which cannot be explained by lesions that only affect the cerebellum. Here we bring together phenotypic, circuit and structural evidence supporting the contribution of cerebellar dysfunction in NDDs and propose that the transcription factor Retinoid-related Orphan Receptor alpha (RORα) provides the missing link underlying both cerebellar and systemic abnormalities observed in NDDs. We present the role of RORα in cerebellar development and how the abnormalities that occur due to RORα deficiency could explain NDD symptoms. We then focus on how RORα is linked to NDDs, particularly ASD and schizophrenia, and how its diverse extra-cerebral actions can explain the systemic components of these diseases. Finally, we discuss how RORα-deficiency is likely a driving force for NDDs through its induction of cerebellar developmental defects, which in turn affect downstream targets, and its regulation of extracerebral systems, such as inflammation, circadian rhythms, and sexual dimorphism.
小脑发育异常日益被认为是神经发育障碍（NDDs）的风险因素，如注意力缺陷多动障碍（ADHD）、自闭症谱系障碍（ASD）和精神分裂症。证据来自自闭症患者的小脑异常，以及在人类患者中发现的一系列影响小脑回路（特别是浦肯野细胞）并与运动功能、学习和社会行为缺陷相关的基因突变；这些特征通常与自闭症和精神分裂症有关。然而，NDDs，如ASD和精神分裂症，也包括全身异常，例如慢性炎症、昼夜节律异常等，这些无法用仅影响小脑的病变来解释。在这里，我们汇集了支持小脑功能障碍在NDDs中作用的表型、回路和结构证据，并提出转录因子视黄酸相关孤儿受体α（RORα）是NDDs中观察到的小脑和全身异常的潜在缺失环节。我们阐述了RORα在小脑发育中的作用，以及由于RORα缺乏而出现的异常如何解释NDD症状。然后，我们关注RORα如何与NDDs相关联，特别是与ASD和精神分裂症相关联，以及其多样的脑外作用如何解释这些疾病的全身组成部分。最后，我们讨论RORα缺乏如何可能通过诱导小脑发育缺陷进而影响下游靶点，以及通过调节脑外系统（如炎症、昼夜节律和性二态性）成为NDDs的驱动力。
