Characterizing Dysfunctional Excitatory-Inhibitory Signaling in Schizophrenia Using Induced Pluripotent Stem Cell-Derived Neurons

Abstract

Schizophrenia (SCZ) is characterized by disrupted excitatory-inhibitory (E-I) balance, particularly within the prefrontal cortex (PFC), arising during neurodevelopment. This thesis investigates synaptic dysfunctions underlying SCZ using human induced pluripotent stem cell (iPSC)-derived glutamatergic and GABAergic co-cultures from two independent patient cohorts. Patch-clamp electrophysiology, calcium imaging, and microelectrode array (MEA) recordings were integrated to assess both single-cell synaptic activity and broader network dynamics, with the aim of elucidating mechanisms of E-I imbalance. Patient-derived co-cultures exhibited heightened network excitability in both cohorts compared to controls, supporting the hypothesis of disrupted E-I balance in SCZ. However, distinct synaptic alterations emerged between cohorts. Cohort A demonstrated increased excitatory synaptic input onto GABAergic neurons, suggesting that altered excitatory-inhibitory integration within the inhibitory cell population may contribute to the observed network phenotype at this developmental stage. Conversely, Cohort B presented a more pronounced enhancement of spontaneous excitatory postsynaptic currents (EPSCs) in glutamatergic neurons, leading to a stronger overactive phenotype.