Innervation modulates the functional connectivity between pancreatic endocrine cells

Direct modulation of pancreatic endocrine cell activity by autonomic innervation has been debated. To resolve this question, we established an in vivo imaging model which also allows chronic and acute neuromodulation. Starting at a stage when zebrafish islet architecture is reminiscent of that in adult rodents, we imaged calcium dynamics simultaneously in multiple islet cell types. We first find that activity coupling between beta cells increases upon glucose exposure. Surprisingly, glucose exposure also increases alpha-alpha, alpha-beta and beta-delta coordination. We further show that both chronic and acute loss of nerve activity diminish activity coupling, as observed upon gap junction depletion. Notably, chronic loss of innervation severely disrupts delta cell activity, suggesting that delta cells receive innervation which coordinates its output. Overall, these data show that innervation plays a vital role in the establishment and maintenance of homotypic and heterotypic cellular connectivity in pancreatic islets, a process critical for islet function.