RESUMO
Alternative splicing regulates trans-synaptic adhesions and synapse development, but supporting in vivo evidence is limited. PTPδ, a receptor tyrosine phosphatase adhering to multiple synaptic adhesion molecules, is associated with various neuropsychiatric disorders; however, its in vivo functions remain unclear. Here, we show that PTPδ is mainly present at excitatory presynaptic sites by endogenous PTPδ tagging. Global PTPδ deletion in mice leads to input-specific decreases in excitatory synapse development and strength. This involves tyrosine dephosphorylation and synaptic loss of IL1RAPL1, a postsynaptic partner of PTPδ requiring the PTPδ-meA splice insert for binding. Importantly, PTPδ-mutant mice lacking the PTPδ-meA insert, and thus lacking the PTPδ interaction with IL1RAPL1 but not other postsynaptic partners, recapitulate biochemical and synaptic phenotypes of global PTPδ-mutant mice. Behaviorally, both global and meA-specific PTPδ-mutant mice display abnormal sleep behavior and non-REM rhythms. Therefore, alternative splicing in PTPδ regulates excitatory synapse development and sleep by modulating a specific trans-synaptic adhesion.
Assuntos
Proteína Acessória do Receptor de Interleucina-1/metabolismo , Proteínas Tirosina Fosfatases/metabolismo , Fases do Sono , Sinapses/metabolismo , Animais , Proteína Acessória do Receptor de Interleucina-1/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Proteínas Tirosina Fosfatases/genética , Sinapses/genéticaRESUMO
BACKGROUND: Given that low income worsens health outcomes, income differences may affect health disparities in weather-related illnesses. The aim of this study was to investigate the association between income levels and prevalence of heat- and cold-related illnesses among Korean adults. METHODS: The current study comprised 535,186 participants with all variables on income and health behaviors. Patients with temperature-related illnesses were defined as individuals with outpatient medical code of heat- and cold-related illnesses. We categorized individual income into three levels: "low" for the fourth quartile (0-25%), "middle" for the second and the third quartiles (25-75%), and "high" for the first quartile (75-100%). To examine income-related health disparities, Cox proportional hazard regression was performed. Hazard ratios (HRs) and 95% CI (confidence interval) for heat- and cold-related illnesses were provided. The model adjusted for age, sex, smoking status, alcohol drinking, exercise, body mass index, hypertension, hyperglycemia, and local income per capita. RESULTS: A total of 5066 (0.95%) and 3302 (0.62%) cases identified patients with heat- and cold-related illnesses, respectively. Compared with high income patients, the adjusted HR for heat-related illnesses was significantly increased in the low income (adjusted HR = 1.103; 95% CI: 1.022-1.191). For cold-related illnesses, participants with low income were likely to have 1.217 times greater likelihood than those with high income (95% CI: 1.107-1.338), after adjusting for other covariates. In the stratified analysis of age (20-64 years and over 65 years) and sex, there was no difference in the likelihood of heat-related illnesses according to income levels. On the other hand, an HR for cold-related illnesses was higher in patients aged 20 to 64 years than in those aged over 65 years. Male with low income had also a higher HR for cold-related illnesses than female with low income. CONCLUSIONS: Our results showed that heat- or cold-related illnesses were more prevalent in Koreans with low income than those with high income. Strategies for low-income subgroups were needed to reduce greater damage due to the influence of extreme temperature events and to implement effective adaptation.
Assuntos
Temperatura Alta , Renda , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , República da Coreia/epidemiologia , Fatores de Risco , Temperatura , Adulto JovemRESUMO
BACKGROUND: Exposure to extremely or moderate low temperatures is associated with increased morbidity and mortality risk. Peripheral vascular disease (PVD) is a slow and progressive circulation disorder. Given that cold temperature causes constriction of the small arteries and veins in the skin, patients who suffer from peripheral circulation problems, like PVD, may be vulnerable to cold injuries. This study aimed to investigate the association between PVD and cold-induced injuries in the winter among Korean adults. We further analyzed the association stratified by body mass index (BMI) classification. METHODS: We used the 2002-2015 National Health Insurance Service-National Sample Cohort data and included a total of 535,186 adults as the study population. Patients with underlying PVD were identified by ICD-10 code I73. Cold-related illnesses were defined by ICD-10 codes (T690, T691, T698, T699, T330 ~ T339, T340 ~ T349, and T350 ~ T357). Body mass index (BMI) was categorized into underweight, normal weight, overweight, and obese. RESULTS: A total of 23.21% (n = 124,224) were PVD patients, and 0.59% (n = 3154) had cold-induced injuries. PVD patients were more likely to be diagnosed with cold injuries, but it was valid only in the underweight or normal weight groups. After adjusting for age, sex, income, cigarette smoking, alcohol consumption, regular exercise, high blood pressure, and hyperglycemia, PVD patients had a significantly increased odds ratio (OR) for cold injuries [adjusted OR = 1.11; 95% confidence intervals (95% CI): 1.01-1.21]. Increased OR for cold injuries in PVD patients was also observed in adults (adjusted OR = 1.14; 95% CI: 1.03-1.25 in Model 2), but not in the elderly. When we classified study subjects into the four BMI groups, the adjusted OR of cold injuries in PVD patients was significant in the underweight group (OR = 1.83; 95% CI, 1.26-2.66) and normal weight group (OR = 1.15; 95% CI, 1.03-1.27), not in those with overweight and obese. In adults, a consistent result was found in adults in the underweight group (OR = 1.63; 95% CI, 1.08-2.47 in Model 2) and normal weight group (OR = 1.19; 95% CI, 1.07-1.33 in Model 2). In the elderly, the adjusted OR for cold injuries was only significant in the underweight group (OR = 3.37; 95% CI, 1.08-10.53 in Model 2). CONCLUSIONS: We found a significant association between PVD and cold-induced injuries in the general population. BMI modified the association. Thus, the association observed appears to be clinically applicable to PVD patients being low to normal BMI.
Assuntos
Lesão por Frio , Doenças Vasculares Periféricas , Adulto , Idoso , Índice de Massa Corporal , Humanos , Sobrepeso , Fatores de Risco , MagrezaRESUMO
Orthotopic liver transplantation has become the treatment of choice for patients with end-stage liver disease. Various early or delayed vascular complications, including arterial pseudoaneurysm, thrombosis, or stenosis, and venous stenosis or occlusion, may lead to graft failure. Early detection and prompt management of such complications are essential to achieve successful transplantation and prevent the need for retransplantation. This report presents differentiating points, using computed tomography and digital subtraction angiography findings and measurement of pressure gradient across the stenotic lesion, that require immediate intervention in patients with inferior vena cava stenosis after orthotopic liver transplantation.
RESUMO
Intrahepatic portosystemic venous shunt (IPSVS) is a rare vascular abnormality that involves abnormal communication between the intrahepatic portal vein and systemic veins, such as the hepatic vein or inferior vena cava. Patients with IPSVS are typically asymptomatic, and IPSVS is incidentally discovered via imaging while evaluating other diseases. However, endovascular closure of the shunt should be considered in symptomatic patients with a high-flow shunt. This report presents a patient with congenital IPSVS with sudden onset hepatic encephalopathy treated using percutaneous transhepatic embolization.
RESUMO
CHD8 (chromodomain helicase DNA-binding protein 8) is a chromatin remodeler associated with autism spectrum disorders. Homozygous Chd8 deletion in mice leads to embryonic lethality, making it difficult to assess whether CHD8 regulates brain development and whether CHD8 haploinsufficiency-related macrocephaly reflects normal CHD8 functions. Here, we report that homozygous conditional knockout of Chd8 restricted to neocortical glutamatergic neurons causes apoptosis-dependent near-complete elimination of neocortical structures. These mice, however, display normal survival and hyperactivity, anxiolytic-like behavior, and increased social interaction. They also show largely normal auditory function and moderately impaired visual and motor functions but enhanced whisker-related somatosensory function. These changes accompany thalamic hyperactivity, revealed by 15.2-Tesla fMRI, and increased intrinsic excitability and decreased inhibitory synaptic transmission in thalamic ventral posterior medial (VPM) neurons involved in somatosensation. These results suggest that excitatory neuronal CHD8 critically regulates neocortical development through anti-apoptotic mechanisms, neocortical elimination distinctly affects cognitive behaviors and sensory-motor functions in mice, and Chd8 haploinsufficiency-related macrocephaly might represent compensatory responses.
Assuntos
Comportamento Animal , Cognição , Proteínas de Ligação a DNA/metabolismo , Atividade Motora , Neocórtex/enzimologia , Neurônios/metabolismo , Núcleos Ventrais do Tálamo/metabolismo , Vibrissas/inervação , Animais , Apoptose , Mapeamento Encefálico , Proteínas de Ligação a DNA/genética , Feminino , Genótipo , Ácido Glutâmico/metabolismo , Imageamento por Ressonância Magnética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neocórtex/patologia , Neocórtex/fisiopatologia , Neurônios/patologia , Fenótipo , Córtex Sensório-Motor/metabolismo , Córtex Sensório-Motor/fisiopatologia , Comportamento Social , Transmissão Sináptica , Núcleos Ventrais do Tálamo/diagnóstico por imagem , Núcleos Ventrais do Tálamo/fisiopatologiaRESUMO
Netrin-G ligand-1 (NGL-1), also known as LRRC4C, is a postsynaptic densities (PSDs)-95-interacting postsynaptic adhesion molecule that interacts trans-synaptically with presynaptic netrin-G1. NGL-1 and its family member protein NGL-2 are thought to promote excitatory synapse development through largely non-overlapping neuronal pathways. While NGL-2 is critical for excitatory synapse development in specific dendritic segments of neurons in an input-specific manner, whether NGL-1 has similar functions is unclear. Here, we show that Lrrc4c deletion in male mice moderately suppresses excitatory synapse development and function, but surprisingly, does so in an input-independent manner. While NGL-1 is mainly detected in the stratum lacunosum moleculare (SLM) layer of the hippocampus relative to the stratum radiatum (SR) layer, NGL-1 deletion leads to decreases in the number of PSDs in both SLM and SR layers in the ventral hippocampus. In addition, both SLM and SR excitatory synapses display suppressed short-term synaptic plasticity in the ventral hippocampus. These morphological and functional changes are either absent or modest in the dorsal hippocampus. The input-independent synaptic changes induced by Lrrc4c deletion involve abnormal translocation of NGL-2 from the SR to SLM layer. These results suggest that Lrrc4c deletion moderately suppresses hippocampal excitatory synapse development and function in an input-independent manner.
RESUMO
Netrin-G ligand-1 (NGL-1), encoded by Lrrc4c, is a post-synaptic adhesion molecule implicated in various brain disorders, including bipolar disorder, autism spectrum disorder, and developmental delay. Although previous studies have explored the roles of NGL-1 in the regulation of synapse development and function, the importance of NGL-1 for specific behaviors and the nature of related neural circuits in mice remain unclear. Here, we report that mice lacking NGL-1 (Lrrc4c-/- ) show strong hyperactivity and anxiolytic-like behavior. They also display impaired spatial and working memory, but normal object-recognition memory and social interaction. c-Fos staining under baseline and anxiety-inducing conditions revealed suppressed baseline neuronal activity as well as limited neuronal activation in widespread brain regions, including the anterior cingulate cortex (ACC), motor cortex, endopiriform nucleus, bed nuclei of the stria terminalis, and dentate gyrus. Neurons in the ACC, motor cortex, and dentate gyrus exhibit distinct alterations in excitatory synaptic transmission and intrinsic neuronal excitability. These results suggest that NGL-1 is important for normal locomotor activity, anxiety-like behavior, and learning and memory, as well as synapse properties and excitability of neurons in widespread brain regions under baseline and anxiety-inducing conditions.
RESUMO
Netrin-G ligand 2 (NGL-2)/LRRC4, implicated in autism spectrum disorders and schizophrenia, is a leucine-rich repeat-containing postsynaptic adhesion molecule that interacts intracellularly with the excitatory postsynaptic scaffolding protein PSD-95 and trans-synaptically with the presynaptic adhesion molecule netrin-G2. Functionally, NGL-2 regulates excitatory synapse development and synaptic transmission. However, whether it regulates synaptic plasticity and disease-related specific behaviors is not known. Here, we report that mice lacking NGL-2 (Lrrc4-/- mice) show suppressed N-Methyl-D-aspartate receptor (NMDAR)-dependent synaptic plasticity in the hippocampus. NGL-2 associates with NMDARs through both PSD-95-dependent and -independent mechanisms. Moreover, Lrrc4-/- mice display mild social interaction deficits and repetitive behaviors that are rapidly improved by pharmacological NMDAR activation. These results suggest that NGL-2 promotes synaptic stabilization of NMDARs, regulates NMDAR-dependent synaptic plasticity, and prevents autistic-like behaviors from developing in mice, supporting the hypothesis that NMDAR dysfunction contributes to autism spectrum disorders.
Assuntos
Transtorno Autístico/patologia , Proteínas do Tecido Nervoso/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Transtorno Autístico/metabolismo , Ciclosserina/farmacologia , Modelos Animais de Doenças , Proteína 4 Homóloga a Disks-Large/química , Proteína 4 Homóloga a Disks-Large/metabolismo , Complexo de Golgi/metabolismo , Hipocampo/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/deficiência , Plasticidade Neuronal/efeitos dos fármacos , Ligação Proteica , Subunidades Proteicas/química , Subunidades Proteicas/metabolismo , Receptores de N-Metil-D-Aspartato/agonistas , Aprendizagem Espacial , Sinapses/metabolismo , Transmissão Sináptica/efeitos dos fármacosRESUMO
Autism spectrum disorders (ASDs) are four times more common in males than in females, but the underlying mechanisms are poorly understood. We characterized sexually dimorphic changes in mice carrying a heterozygous mutation in Chd8 (Chd8+/N2373K) that was first identified in human CHD8 (Asn2373LysfsX2), a strong ASD-risk gene that encodes a chromatin remodeler. Notably, although male mutant mice displayed a range of abnormal behaviors during pup, juvenile, and adult stages, including enhanced mother-seeking ultrasonic vocalization, enhanced attachment to reunited mothers, and isolation-induced self-grooming, their female counterparts do not. This behavioral divergence was associated with sexually dimorphic changes in neuronal activity, synaptic transmission, and transcriptomic profiles. Specifically, female mice displayed suppressed baseline neuronal excitation, enhanced inhibitory synaptic transmission and neuronal firing, and increased expression of genes associated with extracellular vesicles and the extracellular matrix. Our results suggest that a human CHD8 mutation leads to sexually dimorphic changes ranging from transcription to behavior in mice.
Assuntos
Comportamento Animal/fisiologia , Proteínas de Ligação a DNA/biossíntese , Expressão Gênica/fisiologia , Neurônios/fisiologia , Caracteres Sexuais , Animais , Ansiedade de Separação/genética , Ansiedade de Separação/psicologia , Proteínas de Ligação a DNA/genética , Matriz Extracelular/metabolismo , Matriz Extracelular/fisiologia , Feminino , Hipocampo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Apego ao Objeto , Transdução de Sinais/fisiologia , Comportamento Social , Transmissão Sináptica/genética , Transmissão Sináptica/fisiologia , Transcriptoma , Vocalização AnimalRESUMO
Synaptogenic adhesion molecules play critical roles in synapse formation. SALM5/Lrfn5, a SALM/Lrfn family adhesion molecule implicated in autism spectrum disorders (ASDs) and schizophrenia, induces presynaptic differentiation in contacting axons, but its presynaptic ligand remains unknown. We found that SALM5 interacts with the Ig domains of LAR family receptor protein tyrosine phosphatases (LAR-RPTPs; LAR, PTPδ, and PTPσ). These interactions are strongly inhibited by the splice insert B in the Ig domain region of LAR-RPTPs, and mediate SALM5-dependent presynaptic differentiation in contacting axons. In addition, SALM5 regulates AMPA receptor-mediated synaptic transmission through mechanisms involving the interaction of postsynaptic SALM5 with presynaptic LAR-RPTPs. These results suggest that postsynaptic SALM5 promotes synapse development by trans-synaptically interacting with presynaptic LAR-RPTPs and is important for the regulation of excitatory synaptic strength.
Assuntos
Processamento Alternativo/fisiologia , Axônios/metabolismo , Moléculas de Adesão Celular Neuronais/metabolismo , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/metabolismo , Sinapses/metabolismo , Transmissão Sináptica/fisiologia , Animais , Moléculas de Adesão Celular Neuronais/genética , Camundongos , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/genética , Sinapses/genéticaRESUMO
Social deficits are observed in diverse psychiatric disorders, including autism spectrum disorders and schizophrenia. We found that mice lacking the excitatory synaptic signaling scaffold IRSp53 (also known as BAIAP2) showed impaired social interaction and communication. Treatment of IRSp53(-/-) mice, which display enhanced NMDA receptor (NMDAR) function in the hippocampus, with memantine, an NMDAR antagonist, or MPEP, a metabotropic glutamate receptor 5 antagonist that indirectly inhibits NMDAR function, normalized social interaction. This social rescue was accompanied by normalization of NMDAR function and plasticity in the hippocampus and neuronal firing in the medial prefrontal cortex. These results, together with the reduced NMDAR function implicated in social impairments, suggest that deviation of NMDAR function in either direction leads to social deficits and that correcting the deviation has beneficial effects.
Assuntos
Regulação da Expressão Gênica/fisiologia , Mutação/genética , Proteínas do Tecido Nervoso/genética , Receptor de Glutamato Metabotrópico 5/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transtornos do Comportamento Social/genética , Animais , Animais Recém-Nascidos , Estudos de Casos e Controles , Células Cultivadas , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Comportamento Alimentar/efeitos dos fármacos , Comportamento Alimentar/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Asseio Animal/efeitos dos fármacos , Asseio Animal/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Neurônios/ultraestrutura , Reconhecimento Psicológico/efeitos dos fármacos , Reconhecimento Psicológico/fisiologia , Transtornos do Comportamento Social/tratamento farmacológico , Vocalização Animal/efeitos dos fármacos , Vocalização Animal/fisiologiaRESUMO
Synaptic adhesion molecules orchestrate synaptogenesis. The presynaptic leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) regulate synapse development by interacting with postsynaptic Slit- and Trk-like family proteins (Slitrks), which harbour two extracellular leucine-rich repeats (LRR1 and LRR2). Here we identify the minimal regions of the LAR-RPTPs and Slitrks, LAR-RPTPs Ig1-3 and Slitrks LRR1, for their interaction and synaptogenic function. Subsequent crystallographic and structure-guided functional analyses reveal that the splicing inserts in LAR-RPTPs are key molecular determinants for Slitrk binding and synapse formation. Moreover, structural comparison of the two Slitrk1 LRRs reveal that unique properties on the concave surface of Slitrk1 LRR1 render its specific binding to LAR-RPTPs. Finally, we demonstrate that lateral interactions between adjacent trans-synaptic LAR-RPTPs/Slitrks complexes observed in crystal lattices are critical for Slitrk1-induced lateral assembly and synaptogenic activity. Thus, we propose a model in which Slitrks mediate synaptogenic functions through direct binding to LAR-RPTPs and the subsequent lateral assembly of LAR-RPTPs/Slitrks complexes.
Assuntos
Proteínas de Membrana/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Proteínas Tirosina Fosfatases/fisiologia , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/fisiologia , Sinapses/metabolismo , Animais , Sítios de Ligação , Adesão Celular/fisiologia , Células HEK293 , Hipocampo/citologia , Humanos , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Estrutura Terciária de Proteína , Proteínas Tirosina Fosfatases/metabolismo , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/metabolismo , Proteínas Repressoras/metabolismo , Proteínas Repressoras/fisiologia , Sinapses/fisiologiaRESUMO
Severe systemic manifestations of adult onset Still's disease (AOSD) are often fatal and occasionally related to hemophagocytic syndrome (HS). We describe the case of a 49-yr-old woman with AOSD presenting with non-remitting high fever, confusion, jaundice, hepatosplenomegaly, serositis, azotemia, pancytopenia, coagulopathy with disseminated intravascular coagulation (DIC), hyperferritinemia, acute acalculous cholecystitis and ileocolitis noted in computed tomographic images. The patient had a history of herpes zoster developed prior to the admission, but there is no history of diarrhea or abdominal pain. Although bone marrow examination was not performed due to hemorrhagic diathesis, we suspected AOSD-associated HS on the basis of clinical course without detectable infectious agents in cultures or serologic studies. Intravenous immunoglobulin, pulse methylprednisolone, oral cyclosporine A (CsA) and ceftriaxone brought about transient improvement of fever and confusion, but the disease progressed. After increasing CsA dose, all previously mentioned abnormalities disappeared rapidly. Accordingly, we believe that DIC and multiple organ dysfunctions might have been the complications of HS but not that of sepsis, and that CsA can be used as a first-line therapy in case of life-threatening situations.