Methadone interrupts neural growth and function in human cortical organoids

Area of Science:

• Neuroscience
• Developmental Biology
• Pharmacology

Background:

• Prenatal opioid exposure is linked to neonatal abstinence syndrome and later neurological deficits.
• The precise cellular and molecular mechanisms of opioid effects on human fetal brain development remain unclear.

Purpose of the Study:

• To investigate the impact of methadone, a common prenatal opioid, on early human brain development using 3D human cortical organoids (hCOs).
• To examine methadone's effects on neuronal growth, neural network activity, and synaptic transmission.

Main Methods:

• Utilized human cortical organoids (hCOs) as a model system.
• Employed imaging, immunofluorescence, multi-electrode array (MEA), and patch clamp electrophysiology.
• Assessed effects of methadone on organoid growth, neural activity, and synaptic currents.

Main Results:

• Methadone dose-dependently inhibited hCO growth and caused disintegration with prolonged exposure.
• Methadone suppressed spontaneous neuronal firing, with partial recovery upon withdrawal at lower doses.
• Clinically relevant methadone concentrations reduced excitatory postsynaptic currents and attenuated voltage-dependent sodium currents, weakening synaptic transmission.

Conclusions:

• Methadone significantly disrupts neural growth and function during early human brain development.
• The study highlights methadone's detrimental effects on neuronal development and synaptic plasticity.
• Human cortical organoids provide a valuable model for studying prenatal opioid exposure impacts.