Abnormal enteric nervous system and motor activity in the ganglionic proximal bowel of Hirschsprung's disease.
Abnormal enteric nervous system and motor activity in the ganglionic proximal bowel of Hirschsprung's disease.
复制标题
先天性巨结肠症近端肠神经节的肠神经系统和运动活动异常。
DOI：
10.1101/2023.03.08.531750
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Smith-Edwards,KristenM
中科院分区：
文献类型：
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作者：
Edwards,BrianS;Stiglitz,EmmaS;Davis,BrianM;Smith-Edwards,KristenM
先天性巨结肠症（HSCR）是一种先天性缺陷，其中肠神经系统（ENS）在远端肠中不发育，需要手术切除无ENS神经节（“无神经节”）的肠部分，并重新连接具有ENS神经节的“正常”近端肠。不幸的是，许多HSCR患者具有持续的运动障碍（例如，便秘、失禁）和小肠结肠炎，这表明尽管具有ENS神经节，但剩余的肠不正常。在HSCR患者和小鼠的ENS神经支配的近端肠中观察到解剖学和神经化学变化，但没有研究记录ENS活性以定义术后HSCR功能障碍的回路机制。在这里，我们生成了一个HSCR小鼠模型与遗传编码的钙指标映射近端结肠ENS连接体。我们确定了异常的自发性和突触ENS活动在近端结肠GCaMP-Ednrb-/-小鼠HSCR，对应于运动功能障碍。在GCaMP-Ednrb+/-小鼠中也观察到许多HSCR相关缺陷，尽管有完全的ENS神经支配。结果表明，ENS神经支配的肠道功能异常有助于HSCR患者的术后肠道并发症，而不会导致神经节细胞减少症的HSCR相关突变可能会导致没有HSCR诊断的患者的慢性结肠功能障碍。
Hirschsprung’s disease (HSCR) is a congenital defect in which the enteric nervous system (ENS) does not develop in the distal bowel, requiring surgical removal of the portions of bowel without ENS ganglia (‘aganglionic’) and reattachment of the ‘normal’ proximal bowel with ENS ganglia. Unfortunately, many HSCR patients have persistent dysmotility (e.g., constipation, incontinence) and enterocolitis after surgery, suggesting that the remaining bowel is not normal despite having ENS ganglia. Anatomical and neurochemical alterations have been observed in the ENS-innervated proximal bowel from HSCR patients and mice, but no studies have recorded ENS activity to define the circuit mechanisms underlying post-surgical HSCR dysfunction. Here, we generated a HSCR mouse model with a genetically-encoded calcium indicator to map the ENS connectome in the proximal colon. We identified abnormal spontaneous and synaptic ENS activity in proximal colons from GCaMP-Ednrb-/-mice with HSCR that corresponded to motor dysfunction. Many HSCR-associated defects were also observed in GCaMP-Ednrb+/-mice, despite complete ENS innervation. Results suggest that functional abnormalities in the ENS-innervated bowel contribute to post-surgical bowel complications in HSCR patients, and HSCR-related mutations that do not cause aganglionosis may cause chronic colon dysfunction in patients without a HSCR diagnosis.