Smooth muscle-derived neurotrophins regulate development and function of vagal gastrointestinal (GI) afferents

      Brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) regulate development of overlapping populations of vagal sensory neurons. During development, they are expressed in GI smooth muscle, a tissue innervated by vagal mechanoreceptors. To investigate the contributions of this BDNF and NT-3 to vagal development, they were ablated from smooth muscle (smBDNF-KO, smNT-3-KO). As GI vagal afferents signal meal termination (satiation), adult meal patterns were utilized as a functional assay of altered GI vagal development. smNT-3-KO mice exhibited a decrease in meal-induced c-Fos activation in the solitary tract nucleus and area postrema compared to controls, suggesting vagal afferent innervation of the gut was decreased. Consistent with this, smNT-3-KO mice showed increased meal duration, and increased size of their first daily meal, suggesting vagal satiation signaling was reduced. In contrast, smBDNF-KO mice had increased intestinal vagal mechanoreceptor innervation. Increased numbers of vagal sensory neurons and intestinal fiber bundles in the knockout mice suggested this was due to increased survival of intestinal vagal mechanoreceptors. Thus, BDNF may normally suppress survival of these mechanoreceptors, counter to expectations for a growth factor. smBDNF-KO mice ate meals of shorter duration and smaller size than controls, suggesting the increased intestinal innervation provided increased satiation signaling. The opposite effects of smBDNF-KO and smNT-3-KO on GI vagal sensory development/function may result from interactions of smooth muscle-derived BDNF, but not NT-3, with the low affinity nerve growth factor receptor, p75. This receptor is expressed by vagal afferent neurons during development and its activation by BDNF typically results in cell death.
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