The Effects of Neuropeptide Secretin In Early Postnatal Brain Development

Background:  Secretin (Sct) is a peptide hormone that belongs to the secretin/VIP/glucagon peptide family. Secretin was originally isolated in the gastrointestinal system, but it has been found to also function as a neuropeptide in the brain. The receptor for secretin (Sctr) is a member of a G-protein coupled receptor family. Several clinical trials on secretin administration report neurobehavioral improvement in autism and schizophrenia, although the results of these trials remain mostly controversial. To identify the function of secretin in neuronal and behavioral development, we generated Sct and Sctr deficient mice. Sct and Sctr deficient mice are overtly normal and fertile, however, they show autism-related abnormal neuronal and behavioral phenotypes.

Objectives:  In this study, we focused to analyze the role of secretin inearly postnatal brain development.

Methods: Since massive neurogenesis occurs during the early postnatal period, we analyzed hippocampal neurogenesis in mutant pups at postnatal day 21. In addition, we analyzed sensitivity to alcohol toxicity during early postnatal development in mutant mice.

Results:  Interestingly, expression of Sct and Sctr during the early postnatal stages is much higher and more widespread compared to the mature adult brain. Specifically, we observed strong expression in the dentate gyrus of hippocampus and cerebellum during early postnatal stages. We observed impaired survival of neural progenitor cells in Sct and Sctr mutant hippocampus. In Sct and Sctr deficient mice, the number of BrdU-labeled new neurons was significantly decreased and apoptosis of neural progenitor cells was dramatically increased. These data suggest that secretin promotes the survival of neural progenitor cells.

Furthermore, our studies on Sctr deficient mice demonstrated increased sensitivity to alcohol toxicity during the first week of life. Alcohol exposure during brain development induces neuronal cell death in the brain. We identified significant ethanol-induced apoptosis in the external granular layer of the secretin receptor-deficient cerebellum after ethanol treatment. During the early postnatal period, there is a proliferation of granular cell progenitors that reside in the external granular layer. The results suggest that secretin signaling plays a neuroprotective role of neural progenitor cells against the neurotoxicity.

Conclusions:  In summary, we hypothesize that the secretin receptor signaling pathway is required for survival of neural progenitors/immature neurons as well as protection against neurotoxicity that subsequently affects neuropsychological functions throughout the life of the animal. Knowing the mechanism of neuropeptide during postnatal develoment could lead to better understanding of autism.