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Human microglia in brain assembloids display region-specific diversity and respond to hyperexcitable neurons carrying SCN2A mutation.
Microglia critically shape neuronal circuit development and function, yet their region-specific properties and roles in distinct circuits of the human brain remain poorly understood. In this study, we generated region-specific brain organoids (cortical, striatal, and midbrain), each integrated with human microglia, to fill this critical gap. Single-cell RNA sequencing uncovered six distinct microglial subtypes exhibiting unique regional signatures, including a subtype highly enriched for the GABAB receptor gene within striatal organoids. To investigate the contributions of microglia to neural circuitry, we created microglia-incorporated midbrain-striatal assembloids, modeling a core circuit node for many neuropsychiatric disorders, including autism. Using chemogenetics to activate this midbrain-striatal circuit, we observed increased calcium signaling in microglia involving GABAB receptors. Leveraging this model, we examined microglial responses within neural circuits harboring an SCN2A nonsense (C959X) mutation associated with profound autism. Microglia displayed heightened calcium responses to SCN2A mutation-mediated neuronal hyperactivity and engaged in excessive synaptic pruning. These pathological effects were reversed not only by pharmacological inhibition of microglial GABAB receptors but also by knockout of the GABBR1 gene in microglia. Collectively, our findings establish an advanced platform that can be used to dissect human neuroimmune interactions in subcortical regions and to evaluate previously undiscovered therapies, highlighting the important role of microglia in shaping critical circuitry related to neuropsychiatric disorders.
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Isolation and characterization of glial filaments from human brain.
Intermediate (8--9 nm) filaments of human central nervous system astrocytes were isolated from the gliosed white matter of cases of adrenoleukodystrophy (ALD). This hereditary lipidosis is characterized pathologically by demyelination, loss of axons, and replacement of the white matter of the caudal cerebrum by a glial scar. Glial filaments were composed largely of a single protein component with a mol wt of about 49,000 daltons. Smaller components (44,000--39,000 daltons) were detected in some samples, and appear to represent degradation products of the filament protein. Human neurofilaments were isolated from the normal frontal white matter of ALD cases by the standard myelin-free axon technique. Isolated glial and neurofilament proteins comigrated during acrylamide gel electrophoresis in SDS. Polypeptides resulting from cyanogen bromide cleavage of the two filament proteins were the same. Both proteins reacted with rabbit antisera raised against isolated bovine neurofilament protein and human glial fibrillary acidic protein.
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Modeling human telencephalic development and autism-associated SHANK3 deficiency using organoids generated from single neural rosettes.
Human telencephalon is an evolutionarily advanced brain structure associated with many uniquely human behaviors and disorders. However, cell lineages and molecular pathways implicated in human telencephalic development remain largely unknown. We produce human telencephalic organoids from stem cell-derived single neural rosettes and investigate telencephalic development under normal and pathological conditions. We show that single neural rosette-derived organoids contain pallial and subpallial neural progenitors, excitatory and inhibitory neurons, as well as macroglial and periendothelial cells, and exhibit predictable organization and cytoarchitecture. We comprehensively characterize the properties of neurons in SNR-derived organoids and identify transcriptional programs associated with the specification of excitatory and inhibitory neural lineages from a common pool of NPs early in telencephalic development. We also demonstrate that neurons in organoids with a hemizygous deletion of an autism- and intellectual disability-associated gene SHANK3 exhibit intrinsic and excitatory synaptic deficits and impaired expression of several clustered protocadherins. Collectively, this study validates SNR-derived organoids as a reliable model for studying human telencephalic cortico-striatal development and identifies intrinsic, synaptic, and clustered protocadherin expression deficits in human telencephalic tissue with SHANK3 hemizygosity.
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[Light and electron microscopy studies on brain tissue changes in acute experimental oxygen intoxication].
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[Light and electron microscopic observations of sheep scrapie].
Two Suffolk sheep diagnosed as scrapie clinically and epidemiologically were investigated light and electron microscopically. They were female and four years four months of age. Spongiform lesions were found in the gray and white matter of midbrain, pons, medulla oblongata, spinal cord and the cerebellar white matter as well as the cerebral gray and white matter. Ultrastructurally, the spongiform lesions were shown to be caused by vacuolation in neuronal perikarya, vacuolation and/or swelling of neuropil, dilatation of the periaxonal space, and splitting of the myelin sheath followed by the intramyelinic vacuolation. Vacuole in neuronal perikaryon was associated with the enlarged endoplasmic reticulum. Adjacent to the vacuole, enlargement of the rough endoplasmic reticulum and cisterns of Golgi apparatus was observed. The cytoplasmic processes found in the intraneuronal vacuoles were formed by the separation of the cytoplasm caused by the continuous dilatation of the endoplasmic reticulum and cisterns of Golgi apparatus. This indicated that the degeneration of the neuronal perikaryon due to such separation contributed to the formation of the intraneuronal vacuole. Vacuolation and swelling with disappearance of the organelles were also found in astro- and oligodendroglial perikarya. Splitting of myelin sheath and the intramyelinic vacuolation were regarded as primary changes. The latter was supported by the degeneration of oligodendroglias found in this study.
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Studies on the dense-core vesicles in the ontogenesis of locus coeruleus. III. Statistical reconstruction of the diameter distribution of the dense-core vesicles in locus coeruleus during rat ontogenesis.
The method for statistical reconstruction of the diameters of dence-core vesicles, described in the previous work, is applied for studying the changes of these vesicles in the perikarya, the axonal boutons and the neuropile of the rat locus coeruleus during ontogenesis. The data obtained show the presence of the population during the embryonal development and of two populations of dense-core vesicles after birth in the structures studied. This finding is interpreted in connection with the different function of the dense-core vesicles and of the transmitters, respectively, in the development and function of the main noradrenergic nucleus in the brain of mammals -- locus coeruleus.
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Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain.
A population of more than six million people worldwide at high risk of Alzheimer's disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of β-amyloid-(Aβ)-precursor-protein gene. We report AD-like pathology in cerebral organoids grown in vitro from non-invasively sampled strands of hair from 71% of DS donors. The pathology consisted of extracellular diffuse and fibrillar Aβ deposits, hyperphosphorylated/pathologically conformed Tau, and premature neuronal loss. Presence/absence of AD-like pathology was donor-specific (reproducible between individual organoids/iPSC lines/experiments). Pathology could be triggered in pathology-negative T21 organoids by CRISPR/Cas9-mediated elimination of the third copy of chromosome 21 gene BACE2, but prevented by combined chemical β and γ-secretase inhibition. We found that T21 organoids secrete increased proportions of Aβ-preventing (Aβ1-19) and Aβ-degradation products (Aβ1-20 and Aβ1-34). We show these profiles mirror in cerebrospinal fluid of people with DS. We demonstrate that this protective mechanism is mediated by BACE2-trisomy and cross-inhibited by clinically trialled BACE1 inhibitors. Combined, our data prove the physiological role of BACE2 as a dose-sensitive AD-suppressor gene, potentially explaining the dementia delay in ~30% of people with DS. We also show that DS cerebral organoids could be explored as pre-morbid AD-risk population detector and a system for hypothesis-free drug screens as well as identification of natural suppressor genes for neurodegenerative diseases.
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Microperoxisomes in the central nervous system of the postnatal rat.
The distribution of catalase-containing microperoxisomes was studied in the central nervous system of rats during the early postnatal period when the processes of myelination and cell differentiation are active. The regions selected for study included a region previously found in adult animals to contain substantial numbers of reactive microperoxisomes, as well as areas where few such bodies were seen. Microperoxisomes were relatively numerous in all areas during the first two postnatal weeks; at later times they occurred less frequently, or, in some areas, were almost entirely absent. In early postnatal CNS, catalase-positive microperoxisomes were found in all cell types in all regions studied. Neurons of both cerebrum and cerebellum contained catalase-positive microperoxisomes during the first two postnatal weeks; few such neuronal bodies are found in these areas after the third postnatal week. During the period of active myelination, catalase-positive microperoxisomes were found in oligodendrocyte cell bodies, and also in oligodendrocyte processes associated with forming myelin sheaths in all areas. In several areas during the first 3 postnatal weeks, catalase-positive bodies were seen in synaptic terminals, a location where they are seldom observed in mature tissue. Cells of postnatal choroid plexus also were found to contain modest numbers of reactive microperoxisomes.
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Alterations of astrocytic organelles in various lipidoses and allied diseases.
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Mutation of CHD7 impairs the output of neuroepithelium transition that is reversed by the inhibition of EZH2.
Haploinsufficiency of CHD7 (Chromo-Helicase-DNA binding protein 7) causes a severe congenital disease CHARGE syndrome. Brain anomaly such as microcephaly and olfactory bulb agenesis seen in CHARGE patients have not been mimicked in previous animal models. Here, we uncover an indispensable function of CHD7 in the neuroepithelium (NE) but not in the neural stem cells (NSCs) after NE transition. Loss of Chd7 in mouse NE resulted in CHARGE-like brain anomalies due to reduced proliferation and differentiation of neural stem and progenitor cells, which were recapitulated in CHD7 KO human forebrain organoids. Mechanistically, we find that CHD7 activates neural transcription factors by removing the repressive histone mark H3K27me3 and promoting chromatin accessibility. Importantly, neurodevelopmental defects caused by CHD7 loss in human brain organoids and mice were ameliorated by the inhibition of H3K27me3 methyltransferase EZH2. Altogether, by implementing appropriate experimental models, we uncover the pathogenesis of CHD7-associated neurodevelopmental diseases, and identify a potential therapeutic opportunity for CHARGE syndrome.