Many excitatory synapses express Group 1, or Gq coupled, metabotropic glutamate receptors (Gp1 mGluRs) at the periphery of their postsynaptic density. Activation of Gp1 mGluRs typically occurs in ...response to strong activity and triggers long-term plasticity of synaptic transmission in many brain regions, including the neocortex, hippocampus, midbrain, striatum, and cerebellum. Here we focus on mGluR-induced long-term synaptic depression (LTD) and review the literature that implicates Gp1 mGluRs in the plasticity of behavior, learning, and memory. Moreover, recent studies investigating the molecular mechanisms of mGluR-LTD have discovered links to mental retardation, autism, Alzheimer's disease, Parkinson's disease, and drug addiction. We discuss how mGluRs lead to plasticity of neural circuits and how the understanding of the molecular mechanisms of mGluR plasticity provides insight into brain disease.
Cerebral organoids, three-dimensional cultures that model organogenesis, provide a new platform to investigate human brain development. High cost, variability, and tissue heterogeneity limit their ...broad applications. Here, we developed a miniaturized spinning bioreactor (SpinΩ) to generate forebrain-specific organoids from human iPSCs. These organoids recapitulate key features of human cortical development, including progenitor zone organization, neurogenesis, gene expression, and, notably, a distinct human-specific outer radial glia cell layer. We also developed protocols for midbrain and hypothalamic organoids. Finally, we employed the forebrain organoid platform to model Zika virus (ZIKV) exposure. Quantitative analyses revealed preferential, productive infection of neural progenitors with either African or Asian ZIKV strains. ZIKV infection leads to increased cell death and reduced proliferation, resulting in decreased neuronal cell-layer volume resembling microcephaly. Together, our brain-region-specific organoids and SpinΩ provide an accessible and versatile platform for modeling human brain development and disease and for compound testing, including potential ZIKV antiviral drugs.
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•A miniaturized spinning bioreactor for cost-effective culturing of organoids•Generation of brain-region-specific organoids from human iPSCs•ZIKV causes decrease of neuronal cell-layer volume resembling microcephaly•Both African and Asian ZIKV infect neural progenitors in organoids
Zika virus preferentially infects neural progenitors in early stage cortical organoids generated using cost-effective miniaturized spinning bioreactors, resulting in suppressed proliferation, increased cell death, and macroscopic features resembling microcephaly.
The suspected link between infection by Zika virus (ZIKV), a re-emerging flavivirus, and microcephaly is an urgent global health concern. The direct target cells of ZIKV in the developing human fetus ...are not clear. Here we show that a strain of the ZIKV, MR766, serially passaged in monkey and mosquito cells efficiently infects human neural progenitor cells (hNPCs) derived from induced pluripotent stem cells. Infected hNPCs further release infectious ZIKV particles. Importantly, ZIKV infection increases cell death and dysregulates cell-cycle progression, resulting in attenuated hNPC growth. Global gene expression analysis of infected hNPCs reveals transcriptional dysregulation, notably of cell-cycle-related pathways. Our results identify hNPCs as a direct ZIKV target. In addition, we establish a tractable experimental model system to investigate the impact and mechanism of ZIKV on human brain development and provide a platform to screen therapeutic compounds.
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•Zika virus (ZIKV) infects human embryonic cortical neural progenitor cells (hNPCs)•ZIKV-infected hNPCs produce infectious ZIKV particles•ZIKV infection leads to increased cell death of hNPCs•ZIKV infection dysregulates cell cycle and transcription in hNPCs
The suspected link between ZIKV infection and microcephaly is an urgent global health concern. Tang et al. report that ZIKV virus directly infects human cortical neural progenitor cells with high efficiency, resulting in stunted growth of this cell population and transcriptional dysregulation.
Adult neurogenesis, a developmental process of generating functionally integrated neurons, occurs throughout life in the hippocampus of the mammalian brain and showcases the highly plastic nature of ...the mature central nervous system. Significant progress has been made in recent years to decipher how adult neurogenesis contributes to brain functions. Here we review recent findings that inform our understanding of adult hippocampal neurogenesis processes and special properties of adult-born neurons. We further discuss potential roles of adult-born neurons at the circuitry and behavioral levels in cognitive and affective functions and how their dysfunction may contribute to various brain disorders. We end by considering a general model proposing that adult neurogenesis is not a cell-replacement mechanism, but instead maintains a plastic hippocampal neuronal circuit via the continuous addition of immature, new neurons with unique properties and structural plasticity of mature neurons induced by new-neuron integration.
In the embryonic and adult brain, neural stem cells proliferate and give rise to neurons and glia through highly regulated processes. Epigenetic mechanisms - including DNA and histone modifications, ...as well as regulation by non-coding RNAs - have pivotal roles in different stages of neurogenesis. Aberrant epigenetic regulation also contributes to the pathogenesis of various brain disorders. Here, we review recent advances in our understanding of epigenetic regulation in neurogenesis and its dysregulation in brain disorders, including discussion of newly identified DNA cytosine modifications. We also briefly cover the emerging field of epitranscriptomics, which involves modifications of mRNAs and long non-coding RNAs.
Human pluripotent stem cells can be differentiated into cell types that are representative of the central nervous system. Under specific culture conditions, these cells can be induced to ...self-organize into 3D organoids that are reminiscent of the developing brain. Microglia are the resident immune cells of the brain but are derived from a different lineage than neural cells, which presents a challenge to modeling neuroimmune interactions. Although human microglia-like cells can be differentiated from pluripotent stem cells, important considerations include ensuring the identity of microglia, which can be influenced by both the lineage and the local environment, and developing culture methods that promote the integration and survival of diverse cell types in a physiologically relevant model. Recently, several strategies to generate neural organoids with integrated microglia have been demonstrated and provide new opportunities to interrogate interactions among microglia and neurons during development and in response to injury and disease.
In response to the current global health emergency posed by the Zika virus (ZIKV) outbreak and its link to microcephaly and other neurological conditions, we performed a drug repurposing screen of ...∼6,000 compounds that included approved drugs, clinical trial drug candidates and pharmacologically active compounds; we identified compounds that either inhibit ZIKV infection or suppress infection-induced caspase-3 activity in different neural cells. A pan-caspase inhibitor, emricasan, inhibited ZIKV-induced increases in caspase-3 activity and protected human cortical neural progenitors in both monolayer and three-dimensional organoid cultures. Ten structurally unrelated inhibitors of cyclin-dependent kinases inhibited ZIKV replication. Niclosamide, a category B anthelmintic drug approved by the US Food and Drug Administration, also inhibited ZIKV replication. Finally, combination treatments using one compound from each category (neuroprotective and antiviral) further increased protection of human neural progenitors and astrocytes from ZIKV-induced cell death. Our results demonstrate the efficacy of this screening strategy and identify lead compounds for anti-ZIKV drug development.
Granule cells in the dentate gyrus of the hippocampus are thought to be essential to memory function by decorrelating overlapping input patterns (pattern separation). A second excitatory cell type ...in the dentate gyrus, the mossy cell, forms an intricate circuit with granule cells, CA3c pyramidal cells, and local interneurons, but the influence of mossy cells on dentate function is often overlooked. Multiple tetrode recordings, supported by juxtacellular recording techniques, showed that granule cells fired very sparsely, whereas mossy cells in the hilus fired promiscuously in multiple locations and in multiple environments. The activity patterns of these cell types thus represent different environments through distinct computational mechanisms: sparse coding in granule cells and changes in firing field locations in mossy cells.
•A decision tree classifier identified putative granule and mossy cells from tetrodes•Granule cells are rarely active and typically have single firing fields•Juxtacellularly identified mossy cells have multiple firing fields•Granule cells and mossy cells differentially encode distinct environments
Using tetrode and juxtacellular recordings, GoodSmith et al. demonstrate distinct spatial firing and remapping properties of excitatory cell types within the dentate gyrus and CA3c and assess how these cells may support pattern separation in the dentate-CA3 circuit.
In 2015, public awareness of Zika virus (ZIKV) rose in response to alarming statistics of infants with microcephaly being born to women who were infected with the virus during pregnancy, triggering ...global concern over these potentially devastating consequences. Although we have discovered a great deal about the genome and pathogenesis of this reemergent flavivirus since this recent outbreak, we still have much more to learn, including the nature of the virus-host interactions and mechanisms that determine its tropism and pathogenicity in the nervous system, which are in turn shaped by the continual evolution of the virus. Inevitably, we will find out more about the potential long-term effects of ZIKV exposure on the nervous system from ongoing longitudinal studies. Integrating clinical and epidemiological data with a wider range of animal and human cell culture models will be critical to understanding the pathogenetic mechanisms and developing more specific antiviral compounds and vaccines.
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