Kavli Affiliate: Jeremy Willsey
| Authors: Wojciech M Michno, Alyssa Puno, Li Li, Amanda Everitt, Kate McCluskey, Fikri Birey, Saw Htun, Dhriti Nagar, Yuqin Dai, Emily Gurwitz, Jeremy Willsey and Anca M Pasca
| Summary:
Extremely preterm born individuals at < 28 postconceptional weeks (PCW) are at high risk for encephalopathy of prematurity and life-long neuropsychiatric conditions. Clinical studies and animal models of preterm brain injury suggest that encephalopathy of prematurity is strongly associated with exposure to hypoxia and/or inflammation in the perinatal period. Histologic examination of postmortem brain tissue from children born preterm demonstrates decreased numbers of cortical GABAergic interneurons in the cerebral cortex. However, the cellular and molecular mechanisms underlying the decreased numbers of GABAergic interneurons in the cerebral cortex of extremely preterm individuals remain unclear. Here, we developed a dual, complementary human cellular model to study hypoxia-induced interneuronopathies using human forebrain assembloids (hFA) derived from human induced pluripotent stem cells (hiPSCs) and ex vivo human prenatal cerebral cortex at mid-gestation. The hFA are generated through the integration of region-specific neural organoids containing either dorsal forebrain (excitatory) glutamatergic neurons or ventral forebrain (inhibitory) GABAergic interneurons. We discover a substantial reduction in migration of cortical interneurons during exposure to hypoxic stress in both hFA and ex vivo human prenatal cerebral cortex. Next, we identify that this migration defect is restored by supplementation of hypoxic cell culture media with exogenous adrenomedullin (ADM), a peptide hormone member of the calcitonin gene related peptide (CGRP) family. Lastly, we demonstrate that the rescue is mediated through increased activity of the PKA molecular pathway and increased pCREB-dependent expression of GABA receptors. Overall, these findings provide important insights into the cellular mechanisms contributing to cortical interneuron depletion in preterm infants, and pinpoint novel therapeutic molecular pathways with high translational potential for hypoxic encephalopathy of prematurity.