Dysregulated neurodevelopment with altered structural and functional connectivity is believed to underlie many neuropsychiatric disorders, and 'a disease of synapses' is the major hypothesis for the ...biological basis of schizophrenia. Although this hypothesis has gained indirect support from human post-mortem brain analyses and genetic studies, little is known about the pathophysiology of synapses in patient neurons and how susceptibility genes for mental disorders could lead to synaptic deficits in humans. Genetics of most psychiatric disorders are extremely complex due to multiple susceptibility variants with low penetrance and variable phenotypes. Rare, multiply affected, large families in which a single genetic locus is probably responsible for conferring susceptibility have proven invaluable for the study of complex disorders. Here we generated induced pluripotent stem (iPS) cells from four members of a family in which a frameshift mutation of disrupted in schizophrenia 1 (DISC1) co-segregated with major psychiatric disorders and we further produced different isogenic iPS cell lines via gene editing. We showed that mutant DISC1 causes synaptic vesicle release deficits in iPS-cell-derived forebrain neurons. Mutant DISC1 depletes wild-type DISC1 protein and, furthermore, dysregulates expression of many genes related to synapses and psychiatric disorders in human forebrain neurons. Our study reveals that a psychiatric disorder relevant mutation causes synapse deficits and transcriptional dysregulation in human neurons and our findings provide new insight into the molecular and synaptic etiopathology of psychiatric disorders.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Zika virus (ZIKV) directly infects neural progenitors and impairs their proliferation. How ZIKV interacts with the host molecular machinery to impact neurogenesis in vivo is not well understood. ...Here, by systematically introducing individual proteins encoded by ZIKV into the embryonic mouse cortex, we show that expression of ZIKV-NS2A, but not Dengue virus (DENV)-NS2A, leads to reduced proliferation and premature differentiation of radial glial cells and aberrant positioning of newborn neurons. Mechanistically, in vitro mapping of protein-interactomes and biochemical analysis suggest interactions between ZIKA-NS2A and multiple adherens junction complex (AJ) components. Functionally, ZIKV-NS2A, but not DENV-NS2A, destabilizes the AJ complex, resulting in impaired AJ formation and aberrant radial glial fiber scaffolding in the embryonic mouse cortex. Similarly, ZIKA-NS2A, but not DENV-NS2A, reduces radial glial cell proliferation and causes AJ deficits in human forebrain organoids. Together, our results reveal pathogenic mechanisms underlying ZIKV infection in the developing mammalian brain.
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•ZIKV-NS2A, but not DENV-NS2A, depletes RGCs in the embryonic mouse cortex•ZIKV-NS2A expression causes mis-positioning of newborn neurons in the mouse cortex•ZIKA-NS2A interacts with and depletes adherens junction (AJ) complex proteins•ZIKV-NS2A impairs RGC proliferation and AJ formation in human forebrain organoids
Zika virus infects neural stem cells and causes microcephaly. In this study, Yoon et al. showed that NS2A protein encoded by Zika virus, but not by Dengue virus, impairs proliferation of radial glial cells in both embryonic mouse cortex and human forebrain organoids. Mechanistically, ZIKV-NS2A disrupts adherens junction formation.
We previously identified a causal link between a rare patient mutation in DISC1 (disrupted-in-schizophrenia 1) and synaptic deficits in cortical neurons differentiated from isogenic patient-derived ...induced pluripotent stem cells (iPSCs). Here we find that transcripts related to phosphodiesterase 4 (PDE4) signaling are significantly elevated in human cortical neurons differentiated from iPSCs with the DISC1 mutation and that inhibition of PDE4 or activation of the cAMP signaling pathway functionally rescues synaptic deficits. We further generated a knock-in mouse line harboring the same patient mutation in the Disc1 gene. Heterozygous Disc1 mutant mice exhibit elevated levels of PDE4s and synaptic abnormalities in the brain, and social and cognitive behavioral deficits. Pharmacological inhibition of the PDE4 signaling pathway rescues these synaptic, social and cognitive behavioral abnormalities. Our study shows that patient-derived isogenic iPSC and humanized mouse disease models are integral and complementary for translational studies with a better understanding of underlying molecular mechanisms.
Based on experience during our life, neuronal connectivity continuously changes through structural remodeling of synapses. Recent studies have shown that the complex interaction between astrocytes ...and synapses regulates structural synapse remodeling by inducing the formation and elimination of synapses, as well as their functional maturation. Defects in this astrocyte-mediated synapse remodeling cause problems in not only neuronal network activities but also animal behaviors. Moreover, in various neurological disorders, astrocytes have been shown to play central roles in the initiation and progression of synaptic pathophysiology through impaired interactions with synapses. In this review, we will discuss recent studies identifying the novel roles of astrocytes in neuronal circuit remodeling, focusing on synapse formation and elimination. We will also discuss the potential implication of defective astrocytic function in evoking various brain disorders.
•Astrocytes constantly interact with synapses and regulate their activity.•Secreted or contact-mediated astrocytic molecules can induce synaptogenesis.•Astrocytes express phagocytic receptors to selectively eliminate unnecessary synapses.•Neuronal network activity can be modified through synapse formation and elimination by astrocytes.•Defects in synapse remodeling by astrocytes lead to various neurological disorders.
Dopamine system dysfunction is implicated in adolescent-onset neuropsychiatric disorders. Although psychosis symptoms can be alleviated by antipsychotics, cognitive symptoms remain unresponsive and ...novel paradigms investigating the circuit substrates underlying cognitive deficits are critically needed. The frontal cortex and its dopaminergic input from the midbrain are implicated in cognitive functions and undergo maturational changes during adolescence. Here, we used mice carrying mutations in
or
to model mesofrontal dopamine circuit deficiencies and test circuit-based neurostimulation strategies to restore cognitive functions. We found that in a memory-guided spatial navigation task, frontal cortical neurons were activated coordinately at the decision-making point in wild-type but not
-/- mice. Chemogenetic stimulation of midbrain dopamine neurons or optogenetic stimulation of frontal cortical dopamine axons in a limited adolescent period consistently reversed genetic defects in mesofrontal innervation, task-coordinated neuronal activity, and memory-guided decision-making at adulthood. Furthermore, adolescent stimulation of dopamine neurons also reversed the same cognitive deficits in
+/- mice. Our findings reveal common mesofrontal circuit alterations underlying the cognitive deficits caused by two different genes and demonstrate the feasibility of adolescent neurostimulation to reverse these circuit and behavioral deficits. These results may suggest developmental windows and circuit targets for treating cognitive deficits in neurodevelopmental disorders.
Defects in brain development are believed to contribute toward the onset of neuropsychiatric disorders, but identifying specific underlying mechanisms has proven difficult. Here, we took a ...multifaceted approach to investigate why 15q11.2 copy number variants are prominent risk factors for schizophrenia and autism. First, we show that human iPSC-derived neural progenitors carrying 15q11.2 microdeletion exhibit deficits in adherens junctions and apical polarity. This results from haploinsufficiency of CYFIP1, a gene within 15q11.2 that encodes a subunit of the WAVE complex, which regulates cytoskeletal dynamics. In developing mouse cortex, deficiency in CYFIP1 and WAVE signaling similarly affects radial glial cells, leading to their ectopic localization outside of the ventricular zone. Finally, targeted human genetic association analyses revealed an epistatic interaction between CYFIP1 and WAVE signaling mediator ACTR2 and risk for schizophrenia. Our findings provide insight into how CYFIP1 regulates neural stem cell function and may contribute to the susceptibility of neuropsychiatric disorders.
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•hiPSC-derived neural rosettes carrying 15q11.2 CNV exhibit polarity defects•CYFIP1 haploinsufficiency causes polarity defects via WAVE complex destabilization•CYFIP1 and WAVE signaling regulate radial glia cells in the developing mouse cortex•CYFIP1 and ACTR2 interact epistatically to affect risk for schizophrenia
Yoon et al. show that 15q11.2 copy number variants, a risk factor for schizophrenia and autism, result in deficient CYFIP1 and WAVE signaling in cortical neural stem cells.
Childhood neglect and/or abuse can induce mental health conditions with unknown mechanisms. Here, we identified stress hormones as strong inducers of astrocyte-mediated synapse phagocytosis. Using ...in vitro, in vivo, and human brain organoid experiments, we showed that stress hormones increased the expression of the Mertk phagocytic receptor in astrocytes through glucocorticoid receptor (GR). In post-natal mice, exposure to early social deprivation (ESD) specifically activated the GR-MERTK pathway in astrocytes, but not in microglia. The excitatory post-synaptic density in cortical regions was reduced in ESD mice, and there was an increase in the astrocytic engulfment of these synapses. The loss of excitatory synapses, abnormal neuronal network activities, and behavioral abnormalities in ESD mice were largely prevented by ablating GR or MERTK in astrocytes. Our work reveals the critical roles of astrocytic GR-MERTK activation in evoking stress-induced abnormal behaviors in mice, suggesting GR-MERTK signaling as a therapeutic target for stress-induced mental health conditions.
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•Stress hormones induce astrocyte-mediated phagocytosis through GR-MERTK activation•Astrocytic GR-MERTK activation induces excitatory synapse loss in ESD model mice•ESD model mice show abnormal behaviors with increased cortical neuronal firing•Ablating GR-MERTK in astrocytes prevents ESD-evoked synapse loss and behavior symptoms
Early social deprivation induces synaptic and behavioral deficits by unknown mechanisms. Byun et al. reveal that stress hormones induce excessive excitatory synapse elimination via the astrocytic GR-MERTK pathway. Ablating GR-MERTK from astrocytes prevents the loss of excitatory synapses, abnormal neuronal firing, and behavioral symptoms in ESD mice, emphasizing the critical roles of astrocytic phagocytosis in brain physiology and animal behavior.
Quiescence is a hallmark of adult neural stem cells (NSCs) in the mammalian brain, and establishment and maintenance of quiescence is essential for life-long continuous neurogenesis. How NSCs in the ...dentate gyrus (DG) of the hippocampus acquire their quiescence during early postnatal stages and continuously maintain quiescence in adulthood is poorly understood. Here, we show that Hopx-CreERT2-mediated conditional deletion of Nkcc1, which encodes a chloride importer, in mouse DG NSCs impairs both their quiescence acquisition at early postnatal stages and quiescence maintenance in adulthood. Furthermore, PV-CreERT2-mediated deletion of Nkcc1 in PV interneurons in the adult mouse brain leads to activation of quiescent DG NSCs, resulting in an expanded NSC pool. Consistently, pharmacological inhibition of NKCC1 promotes NSC proliferation in both early postnatal and adult mouse DG. Together, our study reveals both cell-autonomous and non-cell-autonomous roles of NKCC1 in regulating the acquisition and maintenance of NSC quiescence in the mammalian hippocampus.
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•Nkcc1 deletion in early postnatal dentate NSCs impairs quiescence acquisition•Nkcc1 deletion in adult dentate quiescent NSCs promotes their activation•Nkcc1 deletion in PV interneurons expands the adult dentate NSC pool•Pharmacological inhibition of NKCC1 promotes dentate NSC proliferation
Quiescence is a hallmark of adult mammalian neural stem cells. Song and colleagues used conditional knockout mice to reveal that NKCC1, a chloride importer, is essential for proliferating neural stem cells to transition into quiescence during early postnatal stages and, furthermore, plays both cell-autonomous and non-cell-autonomous roles in maintaining neural stem cell quiescence in the adult mouse dentate gyrus.
Gene dosage imbalance caused by copy number variations (CNVs) is a prominent contributor to brain disorders. In particular, 15q11.2 CNV duplications and deletions have been associated with autism ...spectrum disorder and schizophrenia, respectively. The mechanism underlying these diametric contributions remains unclear.
We established both loss-of-function and gain-of-function mouse models of Cyfip1, one of four genes within 15q11.2 CNVs. To assess the functional consequences of altered CYFIP1 levels, we performed systematic investigations on behavioral, electrophysiological, and biochemical phenotypes in both mouse models. In addition, we utilized RNA immunoprecipitation sequencing (RIP-seq) analysis to reveal molecular targets of CYFIP1 in vivo.
Cyfip1 loss-of-function and gain-of function mouse models exhibited distinct and shared behavioral abnormalities related to autism spectrum disorder and schizophrenia. RIP-seq analysis identified messenger RNA targets of CYFIP1 in vivo, including postsynaptic NMDA receptor (NMDAR) complex components. In addition, these mouse models showed diametric changes in levels of postsynaptic NMDAR complex components at synapses because of dysregulated protein translation, resulting in bidirectional alteration of NMDAR-mediated signaling. Importantly, pharmacological balancing of NMDAR signaling in these mouse models with diametric Cyfip1 dosages rescues behavioral abnormalities.
CYFIP1 regulates protein translation of NMDAR and associated complex components at synapses to maintain normal synaptic functions and behaviors. Our integrated analyses provide insight into how gene dosage imbalance caused by CNVs may contribute to divergent neuropsychiatric disorders.
Mammary glands develop through primary ductal elongation and side branching to maximize the spatial area. Although primary ducts are generated by bifurcation of terminal end buds, the mechanism ...through which side branching occurs is still largely unclear. Here, we show that inhibitor of DNA-binding 2 (ID2) drives side branch formation through the differentiation of K6
bipotent progenitor cells (BPs) into CD61
luminal progenitor cells (LPs).
-null mice had side-branching defects, along with developmental blockage of the differentiation of K6
BPs into CD61
LPs. Notably, CD61
LPs were found in budding and side branches, but not in terminal end buds. Hormone reconstitution studies using ovariectomized MMTV-hemagglutinin-nuclear localized sequence-tagged
transgenic mice revealed that ID2 is a key mediator of progesterone, which drives luminal lineage differentiation and side branching. Our results suggest that CD61 is a marker of side branches and that ID2 regulates side branch formation by inducing luminal lineage commitment from K6
BPs to CD61
LPs.
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