RESUMO
Activation of T cells is mediated by the engagement of T cell receptors (TCRs) followed by calcium entry via store-operated calcium channels. Here we have shown an additional route for calcium entry into T cells-through the low-voltage-activated T-type CaV3.1 calcium channel. CaV3.1 mediated a substantial current at resting membrane potentials, and its deficiency had no effect on TCR-initiated calcium entry. Mice deficient for CaV3.1 were resistant to the induction of experimental autoimmune encephalomyelitis and had reduced productions of the granulocyte-macrophage colony-stimulating factor (GM-CSF) by central nervous system (CNS)-infiltrating T helper 1 (Th1) and Th17 cells. CaV3.1 deficiency led to decreased secretion of GM-CSF from in vitro polarized Th1 and Th17 cells. Nuclear translocation of the nuclear factor of activated T cell (NFAT) was also reduced in CaV3.1-deficient T cells. These data provide evidence for T-type channels in immune cells and their potential role in shaping the autoimmune response.
Assuntos
Canais de Cálcio Tipo T/genética , Encefalomielite Autoimune Experimental/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Fatores de Transcrição NFATC/metabolismo , Células Th1/imunologia , Células Th17/imunologia , Transporte Ativo do Núcleo Celular/genética , Animais , Autoimunidade/genética , Autoimunidade/imunologia , Cálcio/metabolismo , Citocinas/imunologia , Encefalomielite Autoimune Experimental/imunologia , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/biossíntese , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
Maternally inherited 15q11-13 chromosomal triplications cause a frequent and highly penetrant type of autism linked to increased gene dosages of UBE3A, which encodes a ubiquitin ligase with transcriptional co-regulatory functions. Here, using in vivo mouse genetics, we show that increasing UBE3A in the nucleus downregulates the glutamatergic synapse organizer Cbln1, which is needed for sociability in mice. Epileptic seizures also repress Cbln1 and are found to expose sociability impairments in mice with asymptomatic increases in UBE3A. This Ube3a-seizure synergy maps to glutamate neurons of the midbrain ventral tegmental area (VTA), where Cbln1 deletions impair sociability and weaken glutamatergic transmission. We provide preclinical evidence that viral-vector-based chemogenetic activation of, or restoration of Cbln1 in, VTA glutamatergic neurons reverses the sociability deficits induced by Ube3a and/or seizures. Our results suggest that gene and seizure interactions in VTA glutamatergic neurons impair sociability by downregulating Cbln1, a key node in the expanding protein interaction network of autism genes.
Assuntos
Transtorno Autístico/genética , Regulação para Baixo , Proteínas do Tecido Nervoso/deficiência , Precursores de Proteínas/deficiência , Convulsões/psicologia , Comportamento Social , Ubiquitina-Proteína Ligases/metabolismo , Área Tegmentar Ventral/metabolismo , Animais , Transtorno Autístico/fisiopatologia , Transtorno Autístico/psicologia , Núcleo Celular/metabolismo , Feminino , Ácido Glutâmico/metabolismo , Masculino , Camundongos , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Precursores de Proteínas/biossíntese , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , RNA Mensageiro/metabolismo , Transmissão Sináptica , Ubiquitina-Proteína Ligases/genéticaRESUMO
OBJECTIVE: To investigate the optimal timing of direct acting antiviral (DAA) administration in patients with hepatitis C-associated hepatocellular carcinoma (HCC) undergoing liver transplantation (LT). SUMMARY OF BACKGROUND DATA: In patients with hepatitis C (HCV) associated HCC undergoing LT, the optimal timing of direct-acting antivirals (DAA) administration to achieve sustained virologic response (SVR) and improved oncologic outcomes remains a topic of much debate. METHODS: The United States HCC LT Consortium (2015-2019) was reviewed for patients with primary HCV-associated HCC who underwent LT and received DAA therapy at 20 institutions. Primary outcomes were SVR and HCC recurrence-free survival (RFS). RESULTS: Of 857 patients, 725 were within Milan criteria. SVR was associated with improved 5-year RFS (92% vs 77%, P < 0.01). Patients who received DAAs pre-LT, 0-3âmonths post-LT, and ≥3âmonths post-LT had SVR rates of 91%, 92%, and 82%, and 5-year RFS of 93%, 94%, and 87%, respectively. Among 427 HCV treatment-naïve patients (no previous interferon therapy), patients who achieved SVR with DAAs had improved 5-year RFS (93% vs 76%, P < 0.01). Patients who received DAAs pre-LT, 0-3âmonths post-LT, and ≥3âmonths post-LT had SVR rates of 91%, 93%, and 78% (P < 0.01) and 5-year RFS of 93%, 100%, and 83% (P = 0.01). CONCLUSIONS: The optimal timing of DAA therapy appears to be 0 to 3âmonths after LT for HCV-associated HCC, given increased rates of SVR and improved RFS. Delayed administration after transplant should be avoided. A prospective randomized controlled trial is warranted to validate these results.
Assuntos
Antivirais/administração & dosagem , Carcinoma Hepatocelular/cirurgia , Hepatite C Crônica/tratamento farmacológico , Neoplasias Hepáticas/cirurgia , Transplante de Fígado , Idoso , Benzimidazóis/administração & dosagem , Carbamatos/administração & dosagem , Carcinoma Hepatocelular/virologia , Esquema de Medicação , Combinação de Medicamentos , Feminino , Fluorenos/administração & dosagem , Hepatite C Crônica/complicações , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Humanos , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Pirrolidinas/administração & dosagem , Quinoxalinas/administração & dosagem , Estudos Retrospectivos , Sofosbuvir/administração & dosagem , Sulfonamidas/administração & dosagem , Resposta Viral SustentadaRESUMO
OBJECTIVE: Autism spectrum disorder (ASD) affects 1 in 59 children, yet except for rare genetic causes, the etiology in most ASD remains unknown. In the ASD brain, inflammatory cytokine and transcript profiling shows increased expression of genes encoding mediators of the innate immune response. We evaluated postmortem brain tissue for adaptive immune cells and immune cell-mediated cytotoxic damage that could drive this innate immune response in the ASD brain. METHODS: Standard neuropathology diagnostic methods including histology and immunohistochemistry were extended with automated image segmentation to quantify identified pathologic features in the postmortem brains. RESULTS: We report multifocal perivascular lymphocytic cuffs contain increased numbers of lymphocytes in ~65% of ASD compared to control brains in males and females, across all ages, in most brain regions, and in white and gray matter, and leptomeninges. CD3+ T lymphocytes predominate over CD20+ B lymphocytes and CD8+ over CD4+ T lymphocytes in ASD brains. Importantly, the perivascular cuff lymphocyte numbers correlate to the quantity of astrocyte-derived round membranous blebs. Membranous blebs form as a cytotoxic reaction to lymphocyte attack. Consistent with multifocal immune cell-mediated injury at perivascular cerebrospinal fluid (CSF)-brain barriers, a subset of white matter vessels have increased perivascular space (with jagged contours) and collagen in ASD compared to control brains. CSF-brain barrier pathology is also evident at cerebral cortex pial and ventricular ependymal surfaces in ASD. INTERPRETATION: The findings suggest dysregulated cellular immunity damages astrocytes at foci along the CSF-brain barrier in ASD. ANN NEUROL 2019;86:885-898.
Assuntos
Astrócitos , Transtorno do Espectro Autista , Encéfalo , Linfócitos T , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Astrócitos/imunologia , Astrócitos/patologia , Transtorno do Espectro Autista/imunologia , Transtorno do Espectro Autista/patologia , Encéfalo/imunologia , Encéfalo/patologia , Linfócitos T/imunologia , Linfócitos T/patologia , Bancos de Tecidos/tendênciasRESUMO
Individuals with autism spectrum disorder (ASD) have been found to have a variety of sensory processing deficits. Here we report that maternal immune activation, a known factor for ASD, alters visual acuity in the offspring mice. By intraperitoneally injecting polyinosinic-polycytidylic acid (polyI:C) to induce maternal immune activation during embryonic days 10 to 14, we found that polyI:C treatment impairs visual acuity in young adult offspring mice as examined by their optomotor responses. Concurrently, polyI:C treatment suppresses retinogeniculate axon elimination, resulting in a high fraction of weak optical fibers innervating the relay neurons in the visual thalamus. The results link in-utero maternal inflammation to defective optical fiber pruning and arrested developmental strengthening of single optic fibers which may underlie impaired visual acuity.
Assuntos
Transtorno do Espectro Autista , Efeitos Tardios da Exposição Pré-Natal , Animais , Comportamento Animal , Feminino , Camundongos , Plasticidade Neuronal , Gravidez , Acuidade VisualRESUMO
PURPOSE OF REVIEW: Recent advances in genetic technologies allowed researchers to identify large numbers of candidate risk genes associated with autism spectrum disorder (ASD). Both strongly penetrant rare variants and the accumulation of common variants with much weaker penetrance contribute to the cause of ASD. To identify the highly confident candidate genes, software and resources have been applied, and functional evaluation of the variants has provided further insights for ASD pathophysiology. These studies ultimately identify the molecular and circuit alteration underlying the behavioral abnormalities in ASD. In this review, we introduce the recent genetic and genomic findings and functional approaches for ASD variants providing a deeper understanding of the etiology of ASD. RECENT FINDINGS: Integrated meta-analysis that recruited a larger number of ASD cases has helped to prioritize ASD candidate genes or genetic loci into highly confidence candidate genes for further investigation. Not only coding but also noncoding variants have been recently implicated to confer the risk of ASD. Functional approaches of genes or variants revealed the disruption of specific molecular pathways. Further studies combining ASD genetics and genomics with recent techniques in engineered mouse models show molecular and circuit mechanisms underlying the behavioral deficits in ASD. SUMMARY: Advances in ASD genetics and the following functional studies provide significant insights into ASD pathophysiology at molecular and circuit levels.
Assuntos
Transtorno do Espectro Autista/genética , Predisposição Genética para Doença , Animais , Variações do Número de Cópias de DNA , Modelos Animais de Doenças , Humanos , CamundongosRESUMO
Hemangioblastomas (HBs) are benign, highly vascular tumors, often characterized by loss of function of the von Hippel-Lindau (vHL) gene. They are the most common central nervous system tumor observed in vHL syndrome. Loss of function of the vHL gene creates a "pseudo-hypoxic" state, causing overactivation of hypoxia-inducible factor (HIF) and vascular endothelial growth factor (VEGF)-related pathways. In some cases, HBs can rapidly increase in size during pregnancy to then present acutely, which most frequently occurs after the 20th gestational week. These changes in size usually occur from enlargement of the cystic component of the HB. Due to their preferred location in the posterior fossa near critical structures as well as along the spinal cord, such cases can present with severe neurological deficits, requiring urgent surgical intervention in a multidisciplinary setting. However, the reasons for this acute flare-up during pregnancy remain poorly understood, as are the reasons why this occurs in only a subset of tumors. Unveiling the etiology for this clinical scenario can affect the treatment of HBs, as it will contribute to the understanding of the pathophysiology of such a transformation from a quiescent lesion to a symptomatic one, not only in the setting of pregnancy. Identifying the correct triggers and the conditions initiating and mediating this switch will enable us to develop preventive medications which should allow us to keep the tumor in its quiescent phase. In this pathophysiological review, we investigate the association between HB growth and pregnancy based on an analysis > 40 such published cases. We suggest that the proangiogenic state of pregnancy is the leading etiology for this striking association, and to support the argument, we discuss its potential impact on HIF overexpression in a non-hypoxic manner through activation of the PI3K/Akt/mTOR pathway by proangiogenic factors. Specifically, we discuss the involvement of placental growth factor (PlGF) and its receptor vascular endothelial growth factor receptor 1 (VEGFR-1) in various pathologic processes that can lead to the formation and growth of peritumoral edema and cysts, which are the primary causes for the development of any symptoms in HB. Both PlGF and VEGFR-1 are expressed at increased levels during pregnancy, and both have been reported as part of various pathological processes, including angiogenesis and tumorigenesis. The unique feature that both do essentially not show any significant negative impact on regular physiological processes makes them attractive therapeutic targets since very little side effects are expected. Further research into the effects of anti-PlGF or anti-VEGFR-1 therapy in HB is therefore recommended.
Assuntos
Neoplasias Cerebelares/sangue , Neoplasias Cerebelares/patologia , Hemangioblastoma/sangue , Hemangioblastoma/patologia , Complicações Neoplásicas na Gravidez/sangue , Complicações Neoplásicas na Gravidez/patologia , Neoplasias Cerebelares/etiologia , Feminino , Hemangioblastoma/etiologia , Humanos , Hipóxia , Fator de Crescimento Placentário/sangue , Gravidez , Complicações Neoplásicas na Gravidez/etiologia , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/sangue , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangueRESUMO
Urinary urgency and frequency are common in α-synucleinopathies such as Parkinson disease, Lewy body dementia, and multiple system atrophy. These symptoms cannot be managed with dopamine therapy, and their underlying pathophysiology is unclear. We show that in individuals with Parkinson disease, Lewy body dementia, or multiple system atrophy, α-synuclein pathology accumulates in the lateral collateral pathway, a region of the sacral spinal dorsal horn important for the relay of pelvic visceral afferents. Deposition of α-synuclein in this region may contribute to impaired micturition and/or constipation in Parkinson disease and other α-synucleinopathies.
Assuntos
Encéfalo/metabolismo , Doença por Corpos de Lewy/metabolismo , Atrofia de Múltiplos Sistemas/metabolismo , Doença de Parkinson/metabolismo , Corno Dorsal da Medula Espinal/metabolismo , Incontinência Urinária/metabolismo , Fibras Aferentes Viscerais/metabolismo , alfa-Sinucleína/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/complicações , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Encéfalo/patologia , Feminino , Humanos , Imuno-Histoquímica , Doença por Corpos de Lewy/complicações , Doença por Corpos de Lewy/patologia , Vértebras Lombares , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/complicações , Atrofia de Múltiplos Sistemas/patologia , Doença de Parkinson/complicações , Doença de Parkinson/patologia , Sacro , Medula Espinal/metabolismo , Medula Espinal/patologia , Corno Dorsal da Medula Espinal/patologia , Vértebras Torácicas , Incontinência Urinária/etiologia , Incontinência Urinária/patologia , Fibras Aferentes Viscerais/patologiaRESUMO
The thalamus acts as a conduit for sensory and other information traveling to the cortex. In response to continuous sensory stimulation in vivo, the firing rate of thalamocortical neurons initially increases, but then within a minute firing rate decreases and T-type Ca(2+) channel-dependent action potential burst firing emerges. While neuromodulatory systems could play a role in this inhibitory response, we instead report a novel and cell-autonomous inhibitory mechanism intrinsic to the thalamic relay neuron. Direct intracellular stimulation of thalamocortical neuron firing initially triggered a continuous and high rate of action potential discharge, but within a minute membrane potential (Vm) was hyperpolarized and firing rate to the same stimulus was decreased. This self-inhibition was observed across a wide variety of thalamic nuclei, and in a subset firing mode switched from tonic to bursting. The self-inhibition resisted blockers of intracellular Ca(2+) signaling, Na(+)-K(+)-ATPases, and G protein-regulated inward rectifier (GIRK) channels as implicated in other neuron subtypes, but instead was in part inhibited by an ATP-sensitive K(+) channel blocker. The results identify a new homeostatic mechanism within the thalamus capable of gating excitatory signals at the single-cell level.
Assuntos
Córtex Cerebral/fisiologia , Neurônios/fisiologia , Tálamo/fisiologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Cálcio/metabolismo , Canais de Cálcio Tipo T/genética , Canais de Cálcio Tipo T/metabolismo , Córtex Cerebral/efeitos dos fármacos , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo , Canais KATP/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Neurônios/efeitos dos fármacos , Neurotransmissores/farmacologia , Técnicas de Patch-Clamp , Potássio/metabolismo , Sódio/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Tálamo/efeitos dos fármacos , Técnicas de Cultura de TecidosRESUMO
OBJECTIVE: To determine the frequency of hyperintense cortical signal (HCS) on T1-weighted precontrast magnetic resonance (MR) images in progressive multifocal leukoencephalopathy (PML) patients, its association with seizure risk and immune reconstitution inflammatory syndrome (IRIS), and its pathologic correlate. METHODS: We reviewed clinical data including seizure history, presence of IRIS, and MR imaging scans from PML patients evaluated at our institution between 2003 and 2012. Cases that were diagnosed either using cerebrospinal fluid JC virus (JCV) polymerase chain reaction, brain biopsy, or autopsy, and who had MR images available were included in the analysis (n=49). We characterized pathologic findings in areas of the brain that displayed HCS in 2 patients and compared them with isointense cortex in the same individuals. RESULTS: Of 49 patients, 17 (34.7%) had seizures and 30 (61.2%) had HCS adjacent to subcortical PML lesions on MR images. Of the 17 PML patients with seizures, 15 (88.2%) had HCS compared with 15 of 32 (46.9%) patients without seizures (p=0.006). HCS was associated with seizure development with a relative risk of 4.75 (95% confidence interval=1.2-18.5, p=0.006). Of the 20 patients with IRIS, 16 (80.0%) had HCS compared with 14 of 29 (49.3%) patients without IRIS (p=0.04). On histological examination, HCS areas were associated with striking JCV-associated demyelination of cortical and subcortical U fibers, significant macrophage infiltration, and a pronounced reactive gliosis in the deep cortical layers. INTERPRETATION: Seizures are a frequent complication in PML. HCS is associated with seizures and IRIS, and correlates histologically with JCV focal leukocortical encephalitis.
Assuntos
Córtex Cerebral/patologia , Leucoencefalopatia Multifocal Progressiva/epidemiologia , Imageamento por Ressonância Magnética , Convulsões/epidemiologia , Convulsões/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Córtex Cerebral/fisiopatologia , Encefalite/epidemiologia , Encefalite/patologia , Encefalite/fisiopatologia , Feminino , Humanos , Leucoencefalopatia Multifocal Progressiva/patologia , Leucoencefalopatia Multifocal Progressiva/fisiopatologia , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Convulsões/fisiopatologia , Adulto JovemRESUMO
Leucin-rich, glioma inactivated 1 (LGI1) is a secreted protein linked to human seizures of both genetic and autoimmune aetiology. Mutations in the LGI1 gene are responsible for autosomal dominant temporal lobe epilepsy with auditory features, whereas LGI1 autoantibodies are involved in limbic encephalitis, an acquired epileptic disorder associated with cognitive impairment. We and others previously reported that Lgi1-deficient mice have early-onset spontaneous seizures leading to premature death at 2-3 weeks of age. Yet, where and when Lgi1 deficiency causes epilepsy remains unknown. To address these questions, we generated Lgi1 conditional knockout (cKO) mice using a set of universal Cre-driver mouse lines. Selective deletion of Lgi1 was achieved in glutamatergic pyramidal neurons during embryonic (Emx1-Lgi1cKO) or late postnatal (CaMKIIα-Lgi1cKO) developmental stages, or in gamma amino butyric acidergic (GABAergic) parvalbumin interneurons (PV-Lgi1cKO). Emx1-Lgi1cKO mice displayed early-onset and lethal seizures, whereas CaMKIIα-Lgi1cKO mice presented late-onset occasional seizures associated with variable reduced lifespan. In contrast, neither spontaneous seizures nor increased seizure susceptibility to convulsant were observed when Lgi1 was deleted in parvalbumin interneurons. Together, these data showed that LGI1 depletion restricted to pyramidal cells is sufficient to generate seizures, whereas seizure thresholds were unchanged after depletion in gamma amino butyric acidergic parvalbumin interneurons. We suggest that LGI1 secreted from excitatory neurons, but not parvalbumin inhibitory neurons, makes a major contribution to the pathogenesis of LGI1-related epilepsies. Our data further indicate that LGI1 is required from embryogenesis to adulthood to achieve proper circuit functioning.
Assuntos
Encéfalo/metabolismo , Neurônios/metabolismo , Proteínas/fisiologia , Convulsões/etiologia , Fatores Etários , Animais , Animais Recém-Nascidos , Encéfalo/fisiopatologia , Eletroencefalografia , Embrião de Mamíferos/metabolismo , Neurônios GABAérgicos/metabolismo , Interneurônios/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos , Camundongos Knockout , Proteínas/genética , Células Piramidais/metabolismo , Convulsões/genéticaRESUMO
Hippocampus-dependent learning and memory relies on synaptic plasticity as well as network adaptations provided by the addition of adult-born neurons. We have previously shown that activity-induced intracellular signaling through the Rho family small GTPase Rac1 is necessary in forebrain projection neurons for normal synaptic plasticity in vivo, and here we show that selective loss of neuronal Rac1 also impairs the learning-evoked increase in neurogenesis in the adult mouse hippocampus. Earlier work has indicated that experience elevates the abundance of adult-born neurons in the hippocampus primarily by enhancing the survival of neurons produced just before the learning event. Loss of Rac1 in mature projection neurons did reduce learning-evoked neurogenesis but, contrary to our expectations, these effects were not mediated by altering the survival of young neurons in the hippocampus. Instead, loss of neuronal Rac1 activation selectively impaired a learning-evoked increase in the proliferation and accumulation of neural precursors generated during the learning event itself. This indicates that experience-induced alterations in neurogenesis can be mechanistically resolved into two effects: (1) the well documented but Rac1-independent signaling cascade that enhances the survival of young postmitotic neurons; and (2) a previously unrecognized Rac1-dependent signaling cascade that stimulates the proliferative production and retention of new neurons generated during learning itself.
Assuntos
Células-Tronco Adultas/fisiologia , Aprendizagem em Labirinto/fisiologia , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Neurônios/fisiologia , Neuropeptídeos/fisiologia , Proteínas rac de Ligação ao GTP/fisiologia , Células-Tronco Adultas/citologia , Animais , Antígenos de Diferenciação/genética , Antígenos de Diferenciação/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proliferação de Células , Sobrevivência Celular/fisiologia , Proteínas de Fluorescência Verde/genética , Hipocampo/citologia , Hipocampo/fisiologia , Masculino , Memória de Longo Prazo/fisiologia , Camundongos , Camundongos Knockout , Mitose/fisiologia , Células-Tronco Neurais/citologia , Plasticidade Neuronal/fisiologia , Neurônios/citologia , Neuropeptídeos/genética , Receptor trkB/genética , Receptor trkB/metabolismo , Receptores de AMPA/fisiologia , Percepção Espacial/fisiologia , Proteínas rac de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTPRESUMO
We have previously shown in mice that cytokine-mediated damage to the placenta can temporarily limit the flow of nutrients and oxygen to the fetus. The placental vulnerability is pronounced before embryonic day 11, when even mild immune challenge results in fetal loss. As gestation progresses, the placenta becomes increasingly resilient to maternal inflammation, but there is a narrow window in gestation when the placenta is still vulnerable to immune challenge yet resistant enough to allow for fetal survival. This gestational window correlates with early cortical neurogenesis in the fetal brain. Here, we show that maternal illness during this period selectively alters the abundance and laminar positioning of neuronal subtypes influenced by the Tbr1, Satb2, and Ctip2/Fezf2 patterning axis. The disturbances also lead to a laminar imbalance in the proportions of projection neurons and interneurons in the adult and are sufficient to cause changes in social behavior and cognition. These data illustrate how the timing of an illness-related placental vulnerability causes developmental alterations in neuroanatomical systems and behaviors that are relevant to autism spectrum disorders.
Assuntos
Córtex Cerebral/embriologia , Neurogênese , Doenças Placentárias/patologia , Placenta/patologia , Complicações Infecciosas na Gravidez/patologia , Animais , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Cognição , Transtornos Cognitivos/etiologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Interneurônios/metabolismo , Interneurônios/patologia , Proteínas de Ligação à Região de Interação com a Matriz/genética , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Transtornos Mentais/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Placenta/fisiopatologia , Gravidez , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Comportamento Social , Proteínas com Domínio T , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismoRESUMO
Retinogeniculate connections undergo postnatal refinement in the developing visual system. Here we report that non-ion channel epilepsy gene LGI1 (leucine-rich glioma-inactivated), mutated in human autosomal dominant lateral temporal lobe epilepsy (ADLTE), regulates postnatal pruning of retinal axons in visual relay thalamus. By introducing an ADLTE-associated truncated mutant LGI1 (836delC) or excess full-length LGI1 into transgenic mice, we found that mutant LGI1 blocks, whereas excess LGI1 accelerates, retinogeniculate axon pruning. The normal postnatal single fiber strengthening was arrested by mutant LGI1 and, contrastingly, was enhanced by excess wild-type LGI1. The maximum response of the retinogeniculate synapses, conversely, remained the same in mature LGI1 transgenic mice, indicating that mutant LGI1 blocks, whereas excess wild-type LGI1 promotes, weak axon fiber elimination. Heterozygous deletion of the LGI1 gene, as found in ADLTE patients, inhibited postnatal retinogeniculate synapse elimination, an effect similar to the ADLTE truncated mutant LGI1. The results identify sensory axon remodeling defects in a sensory aura-associated human epilepsy disorder.
Assuntos
Potenciais Pós-Sinápticos Excitadores/fisiologia , Corpos Geniculados/citologia , Corpos Geniculados/crescimento & desenvolvimento , Neurônios/fisiologia , Proteínas/metabolismo , Sinapses/fisiologia , Fatores Etários , Análise de Variância , Animais , Animais Recém-Nascidos , Biofísica , Estimulação Elétrica , Potenciais Pós-Sinápticos Excitadores/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Técnicas In Vitro , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Nervo Óptico/crescimento & desenvolvimento , Nervo Óptico/fisiologia , Técnicas de Patch-Clamp , Proteínas/genética , Tempo de Reação/genética , Receptores de AMPA/metabolismo , Sinapses/genéticaRESUMO
Rare cases of paraneoplastic obesity in children suggest sporadic obesity might also arise from an adaptive immune cell-mediated mechanism. Since the hypothalamus is a central regulator of feeding behavior and energy expenditure, we quantified lymphocytic inflammation in this region in a cohort of obese and non-obese human post-mortem brains. We report that CD8-positive cytotoxic T-cells are increased in hypothalamic median eminence/arcuate nucleus (ME/Arc) and bed nucleus of the stria terminalis in 40% of obese compared to non-obese patients, but not in other hypothalamic nuclei or brain regions. CD8 T-cells were most abundant in individuals with concurrent obesity and diabetes. Markers of cytotoxic T-cell induced damage, activated caspase 3 and poly-ADP ribose, were also elevated in the ME/Arc of obese patients. To provoke CD8 cytotoxic T-cell infiltrates in ventromedial region of hypothalamus in mice we performed stereotactic injections of an adeno-associated virus expressing immunogenic green fluorescent protein or saline. AAV but not saline injections triggered hypothalamic CD8 T-cell infiltrates associated with a rapid weight gain in mice recapitulating the findings in human obesity. This is the first description of the neuropathology of human obesity and when combined with its reconstitution in a mouse model suggests adaptive immunity may drive as much as 40% of the human condition.
Assuntos
Obesidade Infantil , Animais , Humanos , Camundongos , Núcleo Arqueado do Hipotálamo/metabolismo , Linfócitos T CD8-Positivos , Hipotálamo/metabolismo , Obesidade Infantil/metabolismo , Linfócitos TRESUMO
Background: Venous thromboses have been linked to several COVID-19 vaccines, but there is limited information on the Moderna vaccine's effect on the risk of arterial thrombosis. Here we describe a case of post-Moderna COVID-19 vaccination arterial infarct with vaccine-associated diffuse cortical edema that was complicated by refractory intracranial hypertension. Case Summary: 24 hrs after receiving her first dose of the Moderna COVID-19 vaccine, a 30-year-old female developed severe headache. Three weeks later she was admitted with subacute headache and confusion. Imaging initially showed scattered cortical thrombosis with an elevated opening pressure on lumbar puncture. An external ventricular drain was placed, but she continued to have elevated intracranial pressure. Ultimately, she required a hemicraniectomy, but intractable cerebral edema resulted in her death. Pathology was consistent with thrombosis and associated inflammatory response. Conclusion: Though correlational, her medical team surmised that the mRNA vaccine may have contributed to this presentation. The side effects of COVID-19 infection and vaccination are still incompletely understood. Though complications are rare, clinicians should be aware of presentations like this one.
RESUMO
The circuit origins of aggression in autism spectrum disorder remain undefined. Here we report Tac1-expressing glutamatergic neurons in ventrolateral division of ventromedial hypothalamus (VMHvl) drive intermale aggression. Aggression is increased due to increases of Ube3a gene dosage in the VMHvl neurons when modeling autism due to maternal 15q11-13 triplication. Targeted deletion of increased Ube3a copies in VMHvl reverses the elevated aggression adult mice. VMHvl neurons form excitatory synapses onto hypothalamic arcuate nucleus AgRP/NPY neurons through a NRXN1-CBLN1-GluD1 transsynaptic complex and UBE3A impairs this synapse by decreasing Cbln1 gene expression. Exciting AgRP/NPY arcuate neurons leads to feedback inhibition of VMHvl neurons and inhibits aggression. Asymptomatic increases of UBE3A synergize with a heterozygous deficiency of presynaptic Nrxn1 or postsynaptic Grid1 (both ASD genes) to increase aggression. Targeted deletions of Grid1 in arcuate AgRP neurons impairs the VMHvl to AgRP/NPY neuron excitatory synapses while increasing aggression. Chemogenetic/optogenetic activation of arcuate AgRP/NPY neurons inhibits VMHvl neurons and represses aggression. These data reveal that multiple autism genes converge to regulate the VMHvl-arcuate AgRP/NPY glutamatergic synapse. The hypothalamic circuitry implicated by these data suggest impaired excitation of AgRP/NPY feedback inhibitory neurons may explain the increased aggression behavior found in genetic forms of autism.
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Activity-dependent redistribution of ion channels mediates neuronal circuit plasticity and homeostasis, and could provide pro-epileptic or compensatory anti-epileptic responses to a seizure. Thalamocortical neurons transmit sensory information to the cerebral cortex and through reciprocal corticothalamic connections are intensely activated during a seizure. Therefore, we assessed whether a seizure alters ion channel surface expression and consequent neurophysiologic function of thalamocortical neurons. We report a seizure triggers a rapid (<2h) decrease of excitatory postsynaptic current (EPSC)-like current-induced phasic firing associated with increased transient A-type K(+) current. Seizures also rapidly redistributed the A-type K(+) channel subunit Kv4.2 to the neuronal surface implicating a molecular substrate for the increased K(+) current. Glutamate applied in vitro mimicked the effect, suggesting a direct effect of glutamatergic transmission. Importantly, leucine-rich glioma-inactivated-1 (LGI1), a secreted synaptic protein mutated to cause human partial epilepsy, regulated this seizure-induced circuit response. Human epilepsy-associated dominant-negative-truncated mutant LGI1 inhibited the seizure-induced suppression of phasic firing, increase of A-type K(+) current, and recruitment of Kv4.2 surface expression (in vivo and in vitro). The results identify a response of thalamocortical neurons to seizures involving Kv4.2 surface recruitment associated with dampened phasic firing. The results also identify impaired seizure-induced increases of A-type K(+) current as an additional defect produced by the autosomal dominant lateral temporal lobe epilepsy gene mutant that might contribute to the seizure disorder.
Assuntos
Mutação , Inibição Neural/genética , Proteínas/genética , Convulsões/metabolismo , Convulsões/prevenção & controle , Canais de Potássio Shal/antagonistas & inibidores , Canais de Potássio Shal/metabolismo , Animais , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Potenciais Pós-Sinápticos Excitadores/genética , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Camundongos , Camundongos Transgênicos , Condução Nervosa/genética , Neurônios/metabolismo , Neurônios/patologia , Técnicas de Cultura de Órgãos , Transporte Proteico/genética , Proteínas/fisiologia , Convulsões/patologia , Canais de Potássio Shal/genéticaRESUMO
Objective: Enhanced Recovery After Surgery protocols are relatively new in cardiac surgery. Enhanced Recovery After Surgery addresses perioperative analgesia by implementing multimodal pain control regimens that include both opioid and nonopioid components. We investigated the effects of an Enhanced Recovery After Surgery protocol at our institution on postoperative outcomes with particular focus on analgesia. Methods: Single-center retrospective study comparing perioperative opioid use before and after implementation of an Enhanced Recovery After Surgery protocol at our institution. Subjects were divided into 2 cohorts: Enhanced Recovery After Surgery (study group from year 2020) and pre-Enhanced Recovery After Surgery (control group from year 2018). Baseline and perioperative variables including total opioid use from the day of surgery to postoperative day 5 were collected. Opioid use was calculated as morphine milligram equivalents and compared between the 2 cohorts. Results: A total of 466 patients were included: 250 in the Enhanced Recovery After Surgery group and 216 in the pre-Enhanced Recovery After Surgery group. Both groups had similar baseline characteristics, but the Enhanced Recovery After Surgery group had significantly more subjects with intravenous drug use history (P < .0001), endocarditis (P < .0001), and liver disease (P = .007) compared with the pre-Enhanced Recovery After Surgery group. Every day from the day of surgery to postoperative day 5, the Enhanced Recovery After Surgery group had significant reduction (57%) in opioid use compared with the pre-Enhanced Recovery After Surgery group. Total opioid use for the entire length of stay was 259 morphine milligram equivalents in the Enhanced Recovery After Surgery group versus 452 morphine milligram equivalents in the pre-Enhanced Recovery After Surgery group (P < .0001). Subgroup analysis of subjects with intravenous drug use history did not demonstrate a significant reduction in opioid use. Conclusions: Enhanced Recovery After Surgery protocols with an emphasis on multimodal pain management throughout perioperative care are associated with a significant reduction in the postoperative use of opioid analgesics.
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Normal neurodevelopment requires precise expression of the key ubiquitin ligase gene Ube3a. Comparing newly generated mouse models for Ube3a downregulation (models of Angelman syndrome) vs. Ube3a upregulation (models for autism), we find reciprocal effects of Ube3a gene dosage on phenotypes associated with circadian rhythmicity, including the amount of locomotor activity. Consistent with results from neurons in general, we find that Ube3a is imprinted in neurons of the suprachiasmatic nuclei (SCN), the pacemaking circadian brain locus, despite other claims that SCN neurons were somehow exceptional to these imprinting rules. In addition, Ube3a-deficient mice lack the typical drop in wake late in the dark period and have blunted responses to sleep deprivation. Suppression of physical activity by light in Ube3a-deficient mice is not due to anxiety as measured by behavioral tests and stress hormones; quantification of stress hormones may provide a mechanistic link to sleep alteration and memory deficits caused by Ube3a deficiency, and serve as an easily measurable biomarker for evaluating potential therapeutic treatments for Angelman syndrome. We conclude that reduced Ube3a gene dosage affects not only neurodevelopment but also sleep patterns and circadian rhythms.