Dysregulated protocadherin-pathway activity as an intrinsic defect in induced pluripotent stem cell–derived cortical interneurons from subjects with schizophrenia

Abstract

We generated cortical interneurons (cINs) from iPSCs derived from14 healthy controls (HC cINs) and 14 patients with schizophrenia (SCZ cINs). Both HC cINs and SCZ cINs were authentic, fired spontaneously, received functional excitatory inputs from host neurons, and induced GABA-mediated inhibition in host neurons in vivo . However, SCZ cINs had dysregulated expression of protocadherin genes, which lie within documented SCZ loci. Mice lacking protocadherin α showed defective arborization and synaptic density of prefrontal cortex cINs and behavioral abnormalities. SCZ cINs similarly showed defects in synaptic density and arborization, which were reversed by inhibitors of Protein Kinase C, a downstream kinase in the protocadherin pathway. These findings reveal an intrinsic abnormality in SCZ cINs in the absence of any circuit-driven pathology. They also demonstrate the utility of homogenous and functional populations of a relevant neuronal subtype for probing pathogenesis mechanisms during development.

The gamma-Protocadherins regulate the survival of GABAergic interneurons during developmentally-regulated cell death

“…We propose a model in which the extent of PCD among cINs is determined by pro-survival Pcdhg-AKT signaling to provide cINs the advantage to survive and integrate. As variants and dysregulated expression of the human PCDH gene cluster are associated with neurodevelopmental and psychiatric disorders including ASD, Tourette's, and schizophrenia (Anitha et al, 2013;El Hajj et al, 2016;Iossifov et al, 2012; Schizophrenia Working Group of the Psychiatric Genomics, 2014; Shao et al, 2019;Vadodaria et al, 2019), these findings also have relevance for understanding the developmental basis of inhibitory deficits in human disorders.…”

Vascular-Derived SPARC and SerpinE1 Regulate Interneuron Tangential Migration and Accelerate Functional Maturation of Human Stem Cell-Derived Interneurons

“…Previous studies have xenografted hSC-interneurons into a more functionally relevant setting: neonatal mouse cortex. They found that functional maturation rate is prolonged, requiring approximately 7 months (Nicholas et al, 2013;Shao et al, 2019). We then tested the capacity of control and SPARC/SerpinE1-treated ventral organoids to integrate following xenotransplant into immune-compromised (NSG) mouse cortex.…”

“…The timescale for interneuron migration varies widely across species; The process lasts days in mice (Lavdas et al, 1999;Marin and Rubenstein, 2001) and several months in humans (Arshad et al, 2016;Hansen et al, 2013;Ma et al, 2013) . Further, this species difference extends to stem cell derived interneurons where mouse ES-derived interneurons develop rapidly (Au et al, 2013;Maroof et al, 2010;, while hSC-interneuron development is protracted (Nicholas et al, 2013;Shao et al, 2019). Indeed, this limitation has restricted the scope of analysis on hSC-interneurons, hampering detailed functional studies.…”

Focus on Causality in ESC/iPSC-Based Modeling of Psychiatric Disorders

“…Therefore, it would be interesting to know to what degree rescue of PCDH15 or RELN1 in patients' iPSCs would normalize structural abnormalities. Independent support of a critical role of protocadherins in psychiatric disorders was recently obtained by the transplantation of iPSC-derived cortical inhibitory interneurons (cINs) from healthy controls and patients with SCZ into cerebral cortices of mice [62]. Transplants from either group developed undistinguishably into authentic functioning interneurons in vivo and gene expression profiling of in vitro differentiated cINs uncovered only few DEGs.…”