Metabolic contributions to neuronal deficits caused by genomic disruption of schizophrenia risk gene SETD1A

Regulation of neuronal metabolism during early brain development is crucial for directing synaptic plasticity and proper circuit formation. Alterations in neuronal glycolysis or mitochondrial function are associated with several neuropsychiatric disorders, including schizophrenia. Recently, loss-of-function mutations in SETD1A, a histone methyltransferase, have been linked to increased schizophrenia risk and global developmental delay. Here, we show that heterozygous disruption of SETD1A in human induced pluripotent stem cell (hiPSC)-derived neurons results in reduced neurite outgrowth and spontaneous activity, two phenotypes commonly associated with schizophrenia, as well as alterations in metabolic capacity. Furthermore, supplementing culture media with metabolic intermediates ameliorated changes in neurite outgrowth and spontaneous activity, suggesting that metabolic dysfunction contributes to neuronal phenotypes caused by SETD1A haploinsufficiency. These findings highlight a previously unknown connection between SETD1A function, metabolic regulation, and neuron development, and identifies alternative avenues for therapeutic development.

Automated summary

Regulation of neuronal metabolism is crucial for proper brain development. Loss-of-function mutations in SETD1A, a histone methyltransferase, are associated with increased schizophrenia risk and developmental delay. Studies show that SETD1A haploinsufficiency leads to metabolic dysfunction and phenotypes associated with schizophrenia.