Abnormal enteric nervous system and motor activity in the ganglionic proximal bowel of Hirschsprung's disease

Hirschsprungs 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.