HUMAN INDUCED PLURIPOTENT STEM CELL-DERIVED NEURONS CARRYING SCHIZOPHRENIA-ASSOCIATED MUTATIONS IN <EM>SETD1A</EM> DISPLAY INCREASED EXCITABILITY <EM>IN VITRO</EM> AND <EM>IN VIVO</EM>

Schizophrenia is a debilitating psychiatric disorder, affecting approximately 1% of the population. Loss-of-function mutations in the SETD1A gene have been linked to both schizophrenia risk and other neurodevelopmental phenotypes. SETD1A is involved in chromatin remodeling through its function as a H3K4 methyltransferase, but how SETD1A loss-of-function mutations lead to altered brain function remains unclear. In order to gain insight into the functional consequences of loss of SETD1A, this work utilized isogenic human induced pluripotent stem cell (hiPSC) clones that carry heterozygous schizophrenia-associated mutations in SETD1A. Neural precursor cells were established from hiPSCs and differentiated in vitro towards a mixed neuron-astrocyte culture in 8 weeks. Whole-cell patch-clamp recordings of mature hiPSC-derived SETD1A^+/- neurons in vitro revealed a decreased action potential (AP) threshold and half width, and an increased AP amplitude compared to the isogenic control. For in vivo differentiation, hiPSCs were fluorescently labelled and directed towards a neuronal fate through forced overexpression of Ngn2. Differentially labelled SETD1A^+/- and SETD1A^+/+ Ngn2-neurons were mixed in a single cell suspension in a 1:1 ratio and subsequently xenografted into the brains of immunodeficient Rag2^-/- pups (P1-3). Whole-cell patch-clamp slice recordings of labelled hiPSC-derived neurons in the mouse brain revealed a similar phenotype as was observed in vitro, a decreased AP threshold and half width combined with an increased AP amplitude in SETD1A^+/- Ngn2-neurons. These preliminary results suggest that SETD1A loss-of-function mutations could induce increased excitability in hiPSC-derived neurons. Future work will investigate how this affects the integration of hiPSC-derived SETD1A^+/- neurons into functional brain networks.