Pharmacological manipulation of nested oscillations in human iPSC-derived 2D neuronal networks

Dynamically coupled neural networks are fundamental to human cognition and behavior and are disrupted in neurodevelopmental disorders. The formation and dissolution of functional networks is thought to be driven by synchronized oscillatory bursts across large populations of neurons. The mechanisms driving the emergence of these rhythms, known as oscillogenesis, are not well understood, particularly in the human brain. Using multi-electrode arrays, we investigated oscillogenesis in human induced pluripotent stem cell 2D neural cultures at different developmental stages and under pharmacological challenges. We found that cultures exhibited nested oscillations that were reduced by GABAA receptor blockade and emerged earlier when the proportion of GABAergic neurons was increased. Pharmacological manipulations of voltage-gated potassium channels and cholinergic receptors modulated the pattern of nested oscillations. These results reveal the capacity of these 2D cultures to model oscillogenesis, and underscore the need for their continued refinement, paving the way for linking systems-level neural networks to human cognition and disease. • hiPSC-derived neurons develop spontaneous nested oscillations in 2D MEA cultures • Oscillatory and aperiodic activity were characterized via power spectral analysis • Nested oscillations in directed-differentiation neurons rely on inhibitory signaling • Pharmacological manipulations modulate the pattern of nested oscillations • NGN2 induced neurons show distinct oscillatory patterns and drug responses