A systematic characterization of intrinsically formed microglia-like cells during retinal organoid differentiation.

Brain organoids differentiated from human induced pluripotent stem cells provide a unique opportunity to investigate the development, organization and connectivity of neurons in a complex cellular environment. However, organoids usually lack microglia, brain-resident immune cells which are both present in the early human embryonic brain and participate in neuronal circuit development. Here, we find that microglia innately develop in unguided retinal organoid differentiation between week 3 and 4 in 2.5D culture and appear later in floating, non-pigmented, 3D-cystic compartments. We enriched for cystic structures using a low-dosed BMP4 application and performed mass spectrometry, thus defining the protein composition of microglia-containing compartments. We found that cystic compartments expressed both mesenchymal and epithelial markers with microglia enriched in the mesenchymal region. Interestingly, microglia-like cells started to express the border-associated macrophage marker CD163. The preferential localization of human microglia to a mesenchymal compartment provides insight into the behavior and migration of microglia. The model will ultimately allow detailed study of these enigmatic cells and how they enter and distribute within the human brain.

Regulation of Nav1.6-mediated sodium currents underlie the homeostatic control of neuronal intrinsic excitability in the optic tectum of the developing Xenopus laevis tadpole

For individual neurons to function appropriately within a network that is undergoing synaptic reorganization and refinement due to developmental or experience-dependent changes in circuit activity, they must homeostatically adapt their intrinsic excitability to maintain a consistent output despite the changing levels of synaptic input. This homeostatic plasticity of excitability is particularly important for the development of sensory circuits, where subtle deficits in neuronal and circuit function cause developmental disorders including autism spectrum disorder and epilepsy. Despite the critical importance of this process for normal circuit development, the molecular mechanism by which this homeostatic control of intrinsic excitability is regulated is not fully understood. Here, we demonstrate that Xenopus optic tectal neurons express distinct fast, persistent and resurgent Na+ currents. Here, we demonstrate that Xenopus optic tectal neurons express distinct fast, persistent and resurgent Na+ currents. These are regulated with developmental changes in synaptic input, and homeostatically in response to changes in visual input. We show that expression of the voltage-gated Na+ channel subtype Nav1.6 is regulated with changes in intrinsic excitability, that blocking Nav1.6 channels is sufficient to decrease intrinsic excitability. Furthermore, that upregulation of Nav1.6 expression is necessary for experience-dependent increases in Na+ currents and intrinsic excitability. Finally, by examining behaviors that rely on visual and multisensory integration, we extend these findings to show that tight regulation of Na+ channel gene expression during a critical period of tectal circuit development is required for the normal functional development of the tectal circuitry.

Astrocytes in Down Syndrome Across the Lifespan

Down Syndrome (DS) is the most common genetic cause of intellectual disability in which delays and impairments in brain development and function lead to neurological and cognitive phenotypes. Traditionally, a neurocentric approach, focusing on neurons and their connectivity, has been applied to understanding the mechanisms involved in DS brain pathophysiology with an emphasis on how triplication of chromosome 21 leads to alterations in neuronal survival and homeostasis, synaptogenesis, brain circuit development, and neurodegeneration. However, recent studies have drawn attention to the role of non-neuronal cells, especially astrocytes, in DS. Astrocytes comprise a large proportion of cells in the central nervous system (CNS) and are critical for brain development, homeostasis, and function. As triplication of chromosome 21 occurs in all cells in DS (with the exception of mosaic DS), a deeper understanding of the impact of trisomy 21 on astrocytes in DS pathophysiology is warranted and will likely be necessary for determining how specific brain alterations and neurological phenotypes emerge and progress in DS. Here, we review the current understanding of the role of astrocytes in DS, and discuss how specific perturbations in this cell type can impact the brain across the lifespan from early brain development to adult stages. Finally, we highlight how targeting, modifying, and/or correcting specific molecular pathways and properties of astrocytes in DS may provide an effective therapeutic direction given the important role of astrocytes in regulating brain development and function.

Sensorimotor Integration in Childhood Dystonia and Dystonic Cerebral Palsy—A Developmental Perspective

Dystonia is a disorder of sensorimotor integration, involving dysfunction within the basal ganglia, cortex, cerebellum, or their inter-connections as part of the sensorimotor network. Some forms of dystonia are also characterized by maladaptive or exaggerated plasticity. Development of the neuronal processes underlying sensorimotor integration is incompletely understood but involves activity-dependent modeling and refining of sensorimotor circuits through processes that are already taking place in utero and which continue through infancy, childhood, and into adolescence. Several genetic dystonias have clinical onset in early childhood, but there is evidence that sensorimotor circuit development may already be disrupted prenatally in these conditions. Dystonic cerebral palsy (DCP) is a form of acquired dystonia with perinatal onset during a period of rapid neurodevelopment and activity-dependent refinement of sensorimotor networks. However, physiological studies of children with dystonia are sparse. This discussion paper addresses the role of neuroplasticity in the development of sensorimotor integration with particular focus on the relevance of these mechanisms for understanding childhood dystonia, DCP, and implications for therapy selection, including neuromodulation and timing of intervention.

The Drosophila Larval Locomotor Circuit Provides a Model to Understand Neural Circuit Development and Function

It is difficult to answer important questions in neuroscience, such as: “how do neural circuits generate behaviour?,” because research is limited by the complexity and inaccessibility of the mammalian nervous system. Invertebrate model organisms offer simpler networks that are easier to manipulate. As a result, much of what we know about the development of neural circuits is derived from work in crustaceans, nematode worms and arguably most of all, the fruit fly, Drosophila melanogaster. This review aims to demonstrate the utility of the Drosophila larval locomotor network as a model circuit, to those who do not usually use the fly in their work. This utility is explored first by discussion of the relatively complete connectome associated with one identified interneuron of the locomotor circuit, A27h, and relating it to similar circuits in mammals. Next, it is developed by examining its application to study two important areas of neuroscience research: critical periods of development and interindividual variability in neural circuits. In summary, this article highlights the potential to use the larval locomotor network as a “generic” model circuit, to provide insight into mammalian circuit development and function.