Transcription of PIK3CD in human brain and schizophrenia: regulation by proinflammatory cytokines

Abstract

PIK3CD encodes the phosphoinositide 3-kinase (PI3K) catalytic subunit, p110δ, a lipid kinase linked to neurodevelopmental disorders, including schizophrenia (SZ). PIK3CD is regulated at the transcript level through alternate use of 5' untranslated exons (UTRs), promoters, and proinflammatory cytokines. Increases in global PIK3CD expression and downregulation by neuroleptics are observed in SZ, and preclinical efficacy of a p110δ-selective inhibitor is seen in rodent models of risk. Here, we cloned PIK3CD alternative transcripts in human brain and evaluated temporal- and tissue-specific expression. We quantified PIK3CD transcripts in B-lymphoblastoid cells from patients with SZ and examined 5' UTR transcriptional regulation by tumor necrosis factor α (TNFα) and interleukin-1β (IL1β) in patient-derived fibroblasts. We report that PIK3CD transcripts are differentially expressed in human brain in a developmental-specific manner. Transcripts encoding 5' UTRs -2A and alternative exon -1 (Alt1), P37 and AS1 and AS2 were increased in SZ. Alt1, P37, and AS2 were also preferentially expressed in fetal brain, and all transcripts were regulated by TNFα and IL1β. Our findings provide novel insight into the complexity of PIK3CD regulation in human brain, implicate PIK3CD in human neurodevelopment, and identify isoform-specific disruption in SZ.