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Neurodevelopmental disorders are mostly studied using mice as models. However, the mouse brain lacks similar cell types and structures as those of the human brain. In recent years, emergence of three‐dimensional brain organoids derived from human embryonic stem cells or induced pluripotent stem cells allows for controlled monitoring and evaluation of early neurodevelopmental processes and has opened a window for studying various aspects of human brain development. However, such organoids lack original anatomical structure of the brain during maturation, and neurodevelopmental maturation processes that rely on unique cellular interactions and neural network connections are limited. Consequently, organoids are difficult to be used extensively and effectively while modelling later stages of human brain development and disease progression. To address this problem, several methods and technologies have emerged that aim to enhance the sophisticated regulation of brain organoids developmental processes through bioengineering approaches, which may alleviate some of the current limitations. This review discusses recent advances and application areas of human brain organoid culture methods, aiming to generalize optimization strategies for organoid systems, improve the ability to mimic human brain development, and enhance the application value of organoids. [ABSTRACT FROM AUTHOR]

Bioenergetics describe the biochemical processes responsible for energy supply in organisms. When these changes become dysregulated in brain development, multiple neurodevelopmental diseases can occur, implicating bioenergetics as key regulators of neural development. Historically, the discovery of disease processes affecting individual stages of brain development has revealed critical roles that bioenergetics play in generating the nervous system. Bioenergetic-dependent neurodevelopmental disorders include neural tube closure defects, microcephaly, intellectual disability, autism spectrum disorders, epilepsy, mTORopathies, and oncogenic processes. Developmental timing and cell-type specificity of these changes determine the long-term effects of bioenergetic disease mechanisms on brain form and function. Here, we discuss key metabolic regulators of neural progenitor specification, neuronal differentiation (neurogenesis), and gliogenesis. In general, transitions between glycolysis and oxidative phosphorylation are regulated in early brain development and in oncogenesis, and reactive oxygen species (ROS) and mitochondrial maturity play key roles later in differentiation. We also discuss how bioenergetics interface with the developmental regulation of other key neural elements, including the cerebrospinal fluid brain environment. While questions remain about the interplay between bioenergetics and brain development, this review integrates the current state of known key intersections between these processes in health and disease.

The study of inborn errors of neurotransmission has been mostly focused on monoamine disorders, GABAergic and glycinergic defects. The study of the glutamatergic synapse using the same approach than classic neurotransmitter disorders is challenging due to the lack of biomarkers in the CSF. A metabolomic approach can provide both insight into their molecular basis and outline novel therapeutic alternatives. We have performed a semi‐targeted metabolomic analysis on CSF samples from 25 patients with neurogenetic disorders with an important expression in the glutamatergic synapse and 5 controls. Samples from patients diagnosed with MCP2, CDKL5‐, GRINpathies and STXBP1‐related encephalopathies were included. We have performed univariate (UVA) and multivariate statistical analysis (MVA), using Wilcoxon rank‐sum test, principal component analysis (PCA), and OPLS‐DA. By using the results of both analyses, we have identified the metabolites that were significantly altered and that were important in clustering the respective groups. On these, we performed pathway‐ and network‐based analyses to define which metabolic pathways were possibly altered in each pathology. We have observed alterations in the tryptophan and branched‐chain amino acid metabolism pathways, which interestingly converge on LAT1 transporter‐dependency to cross the blood–brain barrier (BBB). Analysis of the expression of LAT1 transporter in brain samples from a mouse model of Rett syndrome (MECP2) revealed a decrease in the transporter expression, that was already noticeable at pre‐symptomatic stages. The study of the glutamatergic synapse from this perspective advances the understanding of their pathophysiology, shining light on an understudied feature as is their metabolic signature. [ABSTRACT FROM AUTHOR]

Bioenergetics describe the biochemical processes responsible for energy supply in organisms. When these changes become dysregulated in brain development, multiple neurodevelopmental diseases can occur, implicating bioenergetics as key regulators of neural development. Historically, the discovery of disease processes affecting individual stages of brain development has revealed critical roles that bioenergetics play in generating the nervous system. Bioenergetic-dependent neurodevelopmental disorders include neural tube closure defects, microcephaly, intellectual disability, autism spectrum disorders, epilepsy, mTORopathies, and oncogenic processes. Developmental timing and cell-type specificity of these changes determine the long-term effects of bioenergetic disease mechanisms on brain form and function. Here, we discuss key metabolic regulators of neural progenitor specification, neuronal differentiation (neurogenesis), and gliogenesis. In general, transitions between glycolysis and oxidative phosphorylation are regulated in early brain development and in oncogenesis, and reactive oxygen species (ROS) and mitochondrial maturity play key roles later in differentiation. We also discuss how bioenergetics interface with the developmental regulation of other key neural elements, including the cerebrospinal fluid brain environment. While questions remain about the interplay between bioenergetics and brain development, this review integrates the current state of known key intersections between these processes in health and disease. • Bioenergetic disruption is implicated in many neurodevelopmental diseases. • Bioenergetics control neural progenitor proliferation and differentiation. • Cell types and differentiation stages depend on specific bioenergetic pathways. [ABSTRACT FROM AUTHOR]

Preserving mitochondrial homeostasis is vital, particularly for the energetically demanding and metabolically active nerve cells. Mitophagy, the selective autophagic removal of mitochondria, stands out as a prominent mechanism for efficient mitochondrial turnover, which is crucial for proper neuronal development and function. Dysfunctional mitochondria and disrupted mitophagy pathways have been linked to a diverse array of neurological disorders. The nematode Caenorhabditis elegans, with its well-defined nervous system, serves as an excellent model to unravel the intricate involvement of mitophagy in developing neurons. This chapter describes the use of Rosella biosensor in C. elegans to monitor neuronal mitophagy, providing a user-friendly platform for screening genes and drugs affecting mitophagic pathways under physiological conditions or in the context of neurodevelopmental pathologies., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)