Related Experiment Video
Updated: May 17, 2026
Hypoxia Alters miRNAs Levels Involved in Non-Mendelian Inheritance of Autism Spectrum Disorder in Mice
Published on: July 11, 2025
Adrenomedullin restores the human cortical interneurons migration defects induced by hypoxia
Alyssa Puno1, Wojciech P Michno1, Li Li1
1Department of Pediatrics, Stanford University, Stanford, United States.
Insights
Hypoxia severely impairs human cortical interneuron migration, crucial for brain development. Adrenomedullin (ADM) treatment rescued these defects, offering a potential therapeutic target for preterm birth brain injury.
Area of Science:
- Neuroscience
- Developmental Biology
- Stem Cell Biology
Background:
- Extremely preterm birth (<28 weeks) causes brain injury, leading to neuropsychiatric diseases.
- Hypoxia and inflammation are key environmental factors disrupting fetal brain development.
- Cortical interneuron migration is vulnerable to disruptions in late gestation.
Purpose of the Study:
- Investigate hypoxia's impact on human cortical interneuron migration.
- Identify molecular mechanisms underlying hypoxia-induced migration deficits.
- Explore adrenomedullin (ADM) as a potential therapeutic for prematurity-related brain injury.
Main Methods:
- Human forebrain assembloids (hFA) from induced pluripotent stem cells (hiPSCs).
- Multi-day confocal live imaging of interneuron migration under hypoxic conditions.
- Transcriptomic analysis to identify gene expression changes.
- ADM supplementation assays and cAMP/PKA pathway analysis.
Main Results:
- Hypoxia significantly reduced human cortical interneuron migration in hFA models.
- Adrenomedullin (ADM) was upregulated in hypoxic conditions.
- Exogenous ADM restored normal interneuron migration.
- ADM activated the cAMP/PKA pathway, rescuing pCREB-dependent GABA receptor expression.
Conclusions:
- This study provides the first direct evidence of hypoxia-induced deficits in human cortical interneuron migration.
- ADM acts protectively by restoring migration through the cAMP/PKA pathway.
- ADM represents a promising therapeutic target for preventing brain injury in extremely preterm infants.
Abstract:
Extremely preterm birth (at <28 postconceptional weeks) leads to brain injury and represents the leading cause of childhood-onset neuropsychiatric diseases. No effective therapeutics exist to reduce the incidence and severity of brain injury of prematurity. Hypoxic events are the most important environmental factor, along with inflammation. Among other developmental processes, the second half of in utero fetal development coincides with the migration of cortical interneurons from the ganglionic eminences into the cortex; this process is thus prone to disruptions following extremely preterm birth. To date, no studies have directly investigated the migration of human cortical inhibitory neurons under hypoxic conditions. Using multi-day confocal live imaging in human forebrain assembloids (hFA) derived from human-induced pluripotent stem cells (hiPSCs) and ex vivo developing human brain tissue, we found a substantial reduction in the migration of hypoxic interneurons. Using transcriptomics, we identified adrenomedullin (ADM) as the gene with the highest fold change increase in expression. Based on previous literature about the protective role of supplemental ADM for other injuries, here, we demonstrated that addition of exogenous ADM to the hypoxic media restores the migration defects of interneurons. Lastly, we showed that one of the mechanisms of protection by ADM is through the activation of the cAMP/PKA pathway and subsequent pCREB-dependent rescued expression of a subset of GABA receptors, which are known to promote migration. Overall, in this manuscript, we provide the first direct evidence for hypoxia-induced deficits in the migration of human cortical interneurons and identify ADM as a possible target for therapeutic development.
