Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA.
Human Pathobiology and OMNI Reverse Translation, Genentech, Inc., San Francisco, CA, USA.
Nat Commun. 2023 Dec 21;14(1):8499. doi: 10.1038/s41467-023-43438-1.
Heterozygous deletions in the ANKS1B gene cause ANKS1B neurodevelopmental syndrome (ANDS), a rare genetic disease characterized by autism spectrum disorder (ASD), attention deficit/hyperactivity disorder, and speech and motor deficits. The ANKS1B gene encodes for AIDA-1, a protein that is enriched at neuronal synapses and regulates synaptic plasticity. Here we report an unexpected role for oligodendroglial deficits in ANDS pathophysiology. We show that Anks1b-deficient mouse models display deficits in oligodendrocyte maturation, myelination, and Rac1 function, and recapitulate white matter abnormalities observed in ANDS patients. Selective loss of Anks1b from the oligodendrocyte lineage, but not from neuronal populations, leads to deficits in social preference and sensory reactivity previously observed in a brain-wide Anks1b haploinsufficiency model. Furthermore, we find that clemastine, an antihistamine shown to increase oligodendrocyte precursor cell maturation and central nervous system myelination, rescues deficits in social preference in 7-month-old Anks1b-deficient mice. Our work shows that deficits in social behaviors present in ANDS may originate from abnormal Rac1 activity within oligodendrocytes.
ANKS1B 基因杂合缺失导致 ANKS1B 神经发育综合征（ANDS），这是一种罕见的遗传疾病，其特征为自闭症谱系障碍（ASD）、注意力缺陷/多动障碍以及言语和运动缺陷。ANKS1B 基因编码 AIDA-1 蛋白，该蛋白在神经元突触中丰富，并调节突触可塑性。在这里，我们报告了少突胶质细胞缺陷在 ANDS 病理生理学中的意外作用。我们表明，Anks1b 缺陷型小鼠模型表现出少突胶质细胞成熟、髓鞘形成和 Rac1 功能缺陷，并重现了 ANDS 患者中观察到的白质异常。选择性地从少突胶质细胞谱系中缺失 Anks1b，但不影响神经元群体，会导致先前在大脑广泛的 Anks1b 半不足模型中观察到的社交偏好和感觉反应缺陷。此外，我们发现克立司丁，一种被证明能增加少突胶质前体细胞成熟和中枢神经系统髓鞘形成的抗组胺药，能挽救 7 月龄 Anks1b 缺陷型小鼠的社交偏好缺陷。我们的工作表明，ANDS 中存在的社交行为缺陷可能源于少突胶质细胞内异常的 Rac1 活性。
