May is Mental Health Awareness month, a time to raise awareness for the roughly 800 million people (and growing) worldwide that live with a psychiatric disorder. These conditions severely impact their lives, are often stigmatized, and carry a suicide risk estimated to be at least tenfold higher than that of the general public.
Compounding the challenges and stigmas associated with these disorders is their heterogeneity: patients with the same diagnosis exhibit extreme variations in their symptoms, the medication(s) they respond to, and their genetics. Greater insights into the cellular and molecular architecture of these disorders are critical not just to understand them, but how they develop—and how to treat them.
For Mental Health Awareness Month, we are highlighting a recent paper that delved deep into the neurodevelopmental causes of schizophrenia (SZ) and has delivered a better understanding of this debilitating disorder.
Marked at conception: Neurodevelopmental disruptions in schizophrenia
Even among psychiatric disorders, SZ is remarkably challenging to study. SZ is a neurodevelopmental disorder, but, as it usually manifests in late adolescence/early adulthood, it can be impossible to determine whether specific transcriptomic and/or epigenomic changes are causative.
To address this, Notaras et al. generated self-assembling cerebral organoids from patients with schizophrenia and controls (1). These three-dimensional constructs help provide a more accurate picture of the transcriptomic, epigenomic, and cellular diversity of the developing cortex. The researchers almost immediately noticed increased apoptosis, decreased neurogenesis, and reduced numbers of cortical neurons in SZ-derived organoids compared to controls.
To get a better view of the specific cell type(s) disrupted in SZ, they performed single cell RNA-sequencing (scRNA-seq) using the Chromium Single Cell 3’ platform to characterize cortical cell–type diversity. Consistent with their earlier findings, the group saw significant reductions in both neurons and neural progenitor cells in SZ- versus control-derived organoids. Interestingly, however, they saw marked enrichments in several non-neuronal cell types, including neuroendothelial and myeloid cells.
Next, researchers created pseudotime trajectories using their scRNA-seq data to glean potential temporal information. Using these methods, they identified SZ organoid–specific depletion of both neuronal and progenitor factors in clusters of cells responsible for neural induction. Coupled with SZ-associated enrichment in neuroendothelial factors, their findings paint a picture where cells are shunted away from neuronal development and funneled into other cell types in SZ organoids.
Digging deeper into their data, the group observed depletions of both BRN2 (which increases late-stage neuronal production) and PTN (which is in close proximity to a SZ-associated locus identified by GWAS and also increases cell survival and growth). Increasing BRN2 expression in SZ organoids resulted in increased numbers of neurons but had no effect on progenitor cell death. However, supplementing SZ organoids with PTN not only increased the number of neurons, but also rescued neurogenesis and decreased progenitor cell death.
Casting light on the path ahead
Schizophrenia, like other psychiatric disorders, is complex. It is heterogeneous, which has, to date, frustrated our best attempts to understand it.
Mental Health Awareness Month is about making others aware of the struggles of patients who suffer from these disorders. It is also a time to shine a light on what people are doing about it—the activists who work to diminish stigmas, the psychiatrists who work towards better patient outcomes, and the researchers striving for new insights and the therapeutics they can provide.
We want to thank the scientists involved in this study, as well as the many other teams working in the psychiatric disorders space, for their work in propelling us towards a better understanding of—and potential treatments for—these debilitating disorders.
- Notaras M, et al. Schizophrenia is defined by cell-specific neuropathology and multiple neurodevelopmental mechanisms in patient-derived cerebral organoids. Mol Psychiatry 27: 1416–1434 (2021). doi: 10.1038/s41380-021-01316-6.