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We analyzed >700,000 single-nucleus RNA sequencing profiles from 106 donors during prenatal and postnatal developmental stages and identified lineage-specific programs that underlie the development of specific subtypes of excitatory cortical neurons, interneurons, glial cell types, and brain vasculature. By leveraging single-nucleus chromatin accessibility data, we delineated enhancer gene regulatory networks and transcription factors that control commitment of specific cortical lineages. By intersecting our results with genetic risk factors for human brain diseases, we identified the cortical cell types and lineages most vulnerable to genetic insults of different brain disorders, especially autism. We find that lineage-specific gene expression programs up-regulated in female cells are especially enriched for the genetic risk factors of autism. Our study captures the molecular progression of cortical lineages across human development.

The human cortex contains inhibitory interneurons derived from the medial ganglionic eminence (MGE), a germinal zone in the embryonic ventral forebrain. How this germinal zone generates sufficient interneurons for the human brain remains unclear. We found that the human MGE (hMGE) contains nests of proliferative neuroblasts with ultrastructural and transcriptomic features that distinguish them from other progenitors in the hMGE. When dissociated hMGE cells are transplanted into the neonatal mouse brain, they reform into nests containing proliferating neuroblasts that generate young neurons that migrate extensively into the mouse forebrain and mature into different subtypes of functional interneurons. Together, these results indicate that the nest organization and sustained proliferation of neuroblasts in the hMGE provide a mechanism for the extended production of interneurons for the human forebrain.

Despite the clinical and genetic heterogeneity of autism, bulk gene expression studies show that changes in the neocortex of autism patients converge on common genes and pathways. However, direct assessment of specific cell types in the brain affected by autism has not been feasible until recently. We used single-nucleus RNA sequencing of cortical tissue from patients with autism to identify autism-associated transcriptomic changes in specific cell types. We found that synaptic signaling of upper-layer excitatory neurons and the molecular state of microglia are preferentially affected in autism. Moreover, our results show that dysregulation of specific groups of genes in cortico-cortical projection neurons correlates with clinical severity of autism. These findings suggest that molecular changes in upper-layer cortical circuits are linked to behavioral manifestations of autism.

Systematic analyses of spatiotemporal gene expression trajectories during organogenesis have been challenging because diverse cell types at different stages of maturation and differentiation coexist in the emerging tissues. We identified discrete cell types as well as temporally and spatially restricted trajectories of radial glia maturation and neurogenesis in developing human telencephalon. These lineage-specific trajectories reveal the expression of neurogenic transcription factors in early radial glia and enriched activation of mammalian target of rapamycin signaling in outer radial glia. Across cortical areas, modest transcriptional differences among radial glia cascade into robust typological distinctions among maturing neurons. Together, our results support a mixed model of topographical, typological, and temporal hierarchies governing cell-type diversity in the developing human telencephalon, including distinct excitatory lineages emerging in rostral and caudal cerebral cortex.

γ-Aminobutyric acid (GABA) is the major inhibitory transmitter in the mature brain but is excitatory in the developing cortex. We found that mouse zona incerta (ZI) projection neurons form a GABAergic axon plexus in neonatal cortical layer 1, making synapses with neurons in both deep and superficial layers. A similar depolarizing GABAergic plexus exists in the developing human cortex. Selectively silencing mouse ZI GABAergic neurons at birth decreased synaptic activity and apical dendritic complexity of cortical neurons. The ZI GABAergic projection becomes inhibitory with maturation and can block epileptiform activity in the adult brain. These data reveal an early-developing GABAergic projection from the ZI to cortical layer 1 that is essential for proper development of cortical neurons and balances excitation with inhibition in the adult cortex.

Many neurologic and psychiatric disorders are marked by imbalances between neural excitation and inhibition. In the cerebral cortex, inhibition is mediated largely by GABAergic (γ-aminobutyric acid-secreting) interneurons, a cell type that originates in the embryonic ventral telencephalon and populates the cortex through long-distance tangential migration. Remarkably, when transplanted from embryos or in vitro culture preparations, immature interneurons disperse and integrate into host brain circuits, both in the cerebral cortex and in other regions of the central nervous system. These features make interneuron transplantation a powerful tool for the study of neurodevelopmental processes such as cell specification, cell death, and cortical plasticity. Moreover, interneuron transplantation provides a novel strategy for modifying neural circuits in rodent models of epilepsy, Parkinson's disease, mood disorders, and chronic pain.

γ-Aminobutyric acid (GABA) is the major inhibitory transmitter in the mature brain but is excitatory in the developing cortex. We found that mouse zona incerta (ZI) projection neurons form a GABAergic axon plexus in neonatal cortical layer 1, making synapses with neurons in both deep and superficial layers. A similar depolarizing GABAergic plexus exists in the developing human cortex. Selectively silencing mouse ZI GABAergic neurons at birth decreased synaptic activity and apical dendritic complexity of cortical neurons. The ZI GABAergic projection becomes inhibitory with maturation and can block epileptiform activity in the adult brain.These data reveal an early-developing GABAergic projection from the ZI to cortical layer 1 that is essential for proper development of cortical neurons and balances excitation with inhibition in the adult cortex. [ABSTRACT FROM AUTHOR]