Excitatory/inhibitory imbalance in schizophrenia : a multimodal approach

Schizophrenia (SZ) is a complex disorder that collectively disrupt normal brain function, significantly impacting patients' social functioning and quality of life. The disorder’s etiology is multifactorial, involving genetic, neurobiological, and environmental factors. Research has emphasized an imbalance in excitatory and inhibitory (E/I) neurotransmission as a core component of SZ pathophysiology. Dysregulation in this balance may stem from abnormalities in the glutamate system, including dysfunctions in voltage-gated sodium channels (VGSCs / NaV) like NaV1.2, or in N-methyl-D-aspartate receptors (NMDARs), both of which play crucial roles in maintaining neuronal excitability and network dynamics. Voltage-gated sodium channels play a crucial role in neuronal excitability, and variants in SCN2A gene (encoding NaV1.2) are associated with SZ. These variants, often resulting in loss-of-function (LoF) effects, have been shown to alter channel kinetics, potentially leading to excitatory/inhibitory dysregulation. In this thesis, I characterized specific schizophrenia-linked SCN2A variants — R850P, V1282F, and S1656P using HEK293T cells as a heterologous expression system. Empoying patch clamp electrophysiology, I demonstrated that all three of them have loss-of-function effect on NaV1.2 function. To further investigate the NMDAR hypothesis of SZ, I generated induced pluripotent stem cells (iPSCs) from patients with SZ and established the protocols to differentiate them into central cortical neurons and directly examine NMDAR function via patch clamp and calcium imaging, aiming to assess E/I balance in patient-specific cellular models. The respective findings underscore that NaV1.2 LoF variants may contribute to E/I imbalance in SZ, and the establishment of patient-specific iPSC models could offer valuable insights into NMDAR-related mechanisms of SZ. These cellular models may provide a platform for testing potential pharmacological interventions. This dual approach suggests that VGSC modulation, along with targeted NMDAR therapies, may hold therapeutic potential in managing the symptoms of schizophrenia.