Department of Neuroscience, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Neurogastroenterol Motil. 2013 Mar;25(3):e233-44. doi: 10.1111/nmo.12083. Epub 2013 Jan 29.
Hirschsprung's disease (HSCR) is a congenital condition in which enteric ganglia, formed from neural crest cells (NCC), are absent from the terminal bowel. Dysmotility and constipation are common features of HSCR that persist following surgical intervention. This persistence suggests that the portion of the colon that remains postoperatively is not able to support normal bowel function. To elucidate the defects that underlie this condition, we utilized a murine model of HSCR.
Mice with NCC-specific deletion of Ednrb were used to measure the neuronal density and neurotransmitter expression in ganglia.
At the site located proximal to the aganglionic region of P21 Ednrb null mice, the neuronal density is significantly decreased and the expression of neurotransmitters is altered compared with het animals. The ganglia in this colonic region are smaller and more isolated while the size of neuronal cell bodies is increased. The percentage of neurons expressing neuronal nNOS and VIP is significantly increased in Ednrb nulls. Conversely, the percentage of choline acetyltransferase (ChAT) expressing neurons is decreased, while Substance P is unchanged between the two genotypes. These changes are limited to the colon and are not detected in the ileum.
CONCLUSIONS & INFERENCES: We demonstrate changes in neuronal density and alterations in the balance of expression of neurotransmitters in the colon proximal to the aganglionic region in Ednrb null mice. The reduced neuronal density and complementary changes in nNOS and ChAT expression may account for the dysmotility seen in HSCR.
先天性巨结肠（HSCR）是一种先天性疾病，其中肠神经节（由神经嵴细胞（NCC）形成）不存在于末端肠道中。运动障碍和便秘是 HSCR 的常见特征，即使在手术后仍会持续存在。这种持续性表明手术后残留的结肠部分无法支持正常的肠道功能。为了阐明导致这种情况的缺陷，我们利用了 HSCR 的小鼠模型。
使用 NCC 特异性缺失 Ednrb 的小鼠来测量神经节中的神经元密度和神经递质表达。
在 P21 Ednrb 基因敲除小鼠的无神经节区域近端部位，神经元密度明显降低，与杂合动物相比，神经递质的表达也发生改变。该结肠区域的神经节更小且更孤立，而神经元细胞体的大小增加。Ednrb 基因敲除小鼠中表达神经元型一氧化氮合酶（nNOS）和 VIP 的神经元比例显著增加。相反，表达胆碱乙酰转移酶（ChAT）的神经元比例减少，而两种基因型之间的 P 物质（Substance P）不变。这些变化仅限于结肠，在回肠中未检测到。
我们证明了 Ednrb 基因敲除小鼠无神经节区域近端结肠中神经元密度的变化以及神经递质表达平衡的改变。神经元密度降低以及 nNOS 和 ChAT 表达的互补变化可能是 HSCR 中运动障碍的原因。
