Examining the Impact of Neurodevelopmental Nicotine Exposure on Cortical Excitation/Inhibition Homeostasis Markers in a Cerebral Organoid Model of Schizophrenia
Kuralay Zhaksylyk, Mohammed H. Sarikahya, Enzo Pérez‐Valenzuela, Daniel B. Hardy, Walter J. Rushlow, Steven R. LavioletteABSTRACT
Schizophrenia (SCZ) is a severe neuropsychiatric disorder thought to arise from an interplay between genetic susceptibility and environmental risk factors, including prenatal nicotine exposure (PNE). Although PNE has been associated with increased risk for SCZ, the underlying mechanisms remain poorly understood. Both SCZ and PNE have independently been linked to excitation/inhibition (E/I) imbalance, suggesting that PNE may exacerbate neurodevelopmental disruptions associated with SCZ. This study employed a cerebral organoid model derived from human induced pluripotent stem cells to examine the impact of PNE on E/I‐related pathways in SCZ. Organoids were chronically exposed to nicotine and analyzed using immunofluorescence and quantitative polymerase chain reaction. Results revealed disease‐associated differences between SCZ and control organoids in a neural progenitor cell marker and several GABAergic, glutamatergic and cholinergic markers. Specifically, SCZ‐derived organoids showed reduced SOX2 and GABAergic differentiation and synthesis markers ( LHX6, GAD1/ GAD67 and SST), increased select GABAergic and glutamatergic markers ( GABRA1, GABRA2, GABBR2 and GRIA1 ), and alterations in multiple cholinergic synthesis, degradation and receptor markers. Effects of nicotine were more modest and limited to CCK, SLC6A1 and SST. These findings support a role for E/I imbalance in SCZ pathophysiology and offer insights into how early‐life exposures may influence disease risk.