RESUMO
Ammonia is considered the main pathogenic toxin in hepatic encephalopathy (HE). However, the molecular mechanisms involved have been disputed. As altered glutamatergic and GABAergic neurotransmission has been reported in HE, we investigated whether four members of the solute carrier 38 (Slc38) family of amino acid transporters-involved in the replenishment of glutamate and GABA-contribute to ammonia neurotoxicity in HE. We show that ammonium ion exerts multiple actions on the Slc38 transporters: It competes with glutamine for the binding to the system N transporters Slc38a3 and Slc38a5, consequently inhibiting bidirectional astroglial glutamine transport. It also competes with H+ , Na+ , and K+ for uncoupled permeation through the same transporters, which may perturb astroglial intracellular pH, membrane potential, and K+ -buffering. Knockdown of Slc38a3 in mice results in cerebral cortical edema and disrupted neurotransmitter synthesis mimicking events contributing to HE development. Finally, in a mouse model of acute liver failure (ALF), we demonstrate the downregulation of Slc38a3 protein, impeded astroglial glutamine release, and cytotoxic edema. Altogether, we demonstrate contribution of Slc38 transporters to the ammonia-induced impairment of glutamine recycling between astrocytes and neurons, a phenomenon underlying acute ammonia neurotoxicity in the setting of ALF.
Assuntos
Sistemas de Transporte de Aminoácidos Neutros/antagonistas & inibidores , Amônia/toxicidade , Astrócitos/patologia , Edema Encefálico/etiologia , Córtex Cerebral/patologia , Doença Hepática Induzida por Substâncias e Drogas/complicações , Regulação da Expressão Gênica/efeitos dos fármacos , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Azoximetano/toxicidade , Edema Encefálico/metabolismo , Edema Encefálico/patologia , Córtex Cerebral/metabolismo , Feminino , Glutamina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transmissão Sináptica , Xenopus laevisRESUMO
GABA signaling sustains fundamental brain functions, from nervous system development to the synchronization of population activity and synaptic plasticity. Despite these pivotal features, molecular determinants underscoring the rapid and cell-autonomous replenishment of the vesicular neurotransmitter GABA and its impact on synaptic plasticity remain elusive. Here, we show that genetic disruption of the glutamine transporter Slc38a1 in mice hampers GABA synthesis, modifies synaptic vesicle morphology in GABAergic presynapses and impairs critical period plasticity. We demonstrate that Slc38a1-mediated glutamine transport regulates vesicular GABA content, induces high-frequency membrane oscillations and shapes cortical processing and plasticity. Taken together, this work shows that Slc38a1 is not merely a transporter accumulating glutamine for metabolic purposes, but a key component regulating several neuronal functions.
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Sistema A de Transporte de Aminoácidos/metabolismo , Encéfalo/fisiologia , Neurônios GABAérgicos/fisiologia , Plasticidade Neuronal/fisiologia , Transmissão Sináptica/fisiologia , Animais , CamundongosRESUMO
Progressive myoclonus epilepsy is a heterogeneous group of disorders characterized by myoclonic and tonic-clonic seizures, ataxia and cognitive decline. We here present two affected brothers. At 9 months of age the elder brother developed ataxia and myoclonic jerks. In his second year he lost the ability to walk and talk, and he developed drug-resistant progressive myoclonus epilepsy. The cerebrospinal fluid level of glutamate was decreased while glutamine was increased. His younger brother manifested similar symptoms from 6 months of age. By exome sequencing of the proband we identified a novel homozygous frameshift variant in the potassium channel tetramerization domain 7 (KCTD7) gene (NM_153033.1:c.696delT: p.F232fs), which results in a truncated protein. The identified F232fs variant is inherited in an autosomal recessive manner, and the healthy consanguineous parents carry the variant in a heterozygous state. Bioinformatic analyses and structure modelling showed that KCTD7 is a highly conserved protein, structurally similar to KCTD5 and several voltage-gated potassium channels, and that it may form homo- or heteromultimers. By heterologous expression in Xenopus laevis oocytes, we demonstrate that wild-type KCTD7 hyperpolarizes cells in a K+ dependent manner and regulates activity of the neuronal glutamine transporter SAT2 (Slc38a2), while the F232fs variant impairs K+ fluxes and obliterates SAT2-dependent glutamine transport. Characterization of four additional disease-causing variants (R94W, R184C, N273I, Y276C) bolster these results and reveal the molecular mechanisms involved in the pathophysiology of KCTD7-related progressive myoclonus epilepsy. Thus, our data demonstrate that KCTD7 has an impact on K+ fluxes, neurotransmitter synthesis and neuronal function, and that malfunction of the encoded protein may lead to progressive myoclonus epilepsy.
Assuntos
Glutamina/metabolismo , Epilepsias Mioclônicas Progressivas/genética , Neurônios/metabolismo , Canais de Potássio/genética , Potássio/metabolismo , Sistema A de Transporte de Aminoácidos/metabolismo , Animais , Transporte Biológico , Pré-Escolar , Consanguinidade , Evolução Fatal , Humanos , Masculino , Oócitos , Linhagem , Arábia Saudita , Irmãos , Xenopus laevisRESUMO
BACKGROUND: To examine whether delirium in hip fracture patients was associated with changes in the levels of amino acids and/or monoamine metabolites in cerebrospinal fluid (CSF) and serum. METHODS: In this prospective cohort study, 77 patients admitted with an acute hip fracture to Oslo University Hospital, Norway, were studied. The concentrations of amino acids in CSF and serum were determined by high performance liquid chromatography. The patients were assessed daily for delirium by the Confusion Assessment Method (pre-operatively and post-operative day 1-5 (all) or until discharge (delirious patients)). Pre-fracture dementia status was decided by an expert panel. Serum was collected pre-operatively and CSF immediately before spinal anesthesia. RESULTS: Fifty-three (71 %) hip fracture patients developed delirium. In hip fracture patients without dementia (n = 39), those with delirium had significantly higher CSF levels of tryptophan (40 % higher), tyrosine (60 % higher), phenylalanine (59 % higher) and the monoamine metabolite 5-hydroxyindoleacetate (23 % higher) compared to those without delirium. The same amino acids were also higher in CSF in delirious patients with dementia (n = 38). The correlations between serum and CSF amino acid levels were poor. CONCLUSION: Higher CSF levels of monoamine precursors in hip fracture patients with delirium suggest a higher monoaminergic activity in the central nervous system during delirium in this patient group.
Assuntos
Delírio , Demência , Fraturas do Quadril , Indóis/metabolismo , Fenilalanina/metabolismo , Triptofano/metabolismo , Tirosina/metabolismo , Idoso , Idoso de 80 Anos ou mais , Cromatografia Líquida/métodos , Delírio/sangue , Delírio/líquido cefalorraquidiano , Delírio/diagnóstico , Delírio/etiologia , Demência/complicações , Demência/diagnóstico , Demência/metabolismo , Feminino , Fraturas do Quadril/sangue , Fraturas do Quadril/líquido cefalorraquidiano , Fraturas do Quadril/complicações , Fraturas do Quadril/cirurgia , Humanos , Masculino , Noruega , Cuidados Pré-Operatórios/métodos , Estudos Prospectivos , Escalas de Graduação Psiquiátrica , Reprodutibilidade dos TestesRESUMO
The aerobic glycolytic pathway, boosting lactate formation, and glutamine addiction are two hallmarks of cancer pathophysiology. Consistent with this, several cell membrane glutamine transporters, belonging to different solute carrier (SLC) families, have been shown to be upregulated in a cell-specific manner to furnish the cells with glutamine and glutamine-derived metabolic intermediates. Among them, the system A transporter Slc38a1 has a higher affinity for glutamine compared to other SLC transporters, and it undergoes highly multifaceted regulation at gene and protein levels. The current study aimed to investigate the functional role of Slc38a1 in the proliferation and maturation of the mouse tongue epithelium. Secondly, we aimed to examine the expression of SLC38A1 and its regulation in human tongue oral squamous cell carcinoma (OTSCC). Employing Slc38a1 wild-type and knockout mice, we showed that Slc38a1 was not directly linked to the regulation of the proliferation and differentiation of the mouse tongue epithelium. External transcriptomic datasets and Western blot analyses showed upregulation of SLC38A1 mRNA/protein in human OTSCC and oral cancer cell lines as compared to the corresponding controls. Further, an investigation of external datasets indicated that mechanisms other than the amplification of the SLC38A1 chromosomal locus or hypomethylation of the SLC38A1 promoter region might be important for the upregulation of SLC38A1 in OTSCC.
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BACKGROUND: The aetiology of delirium is not known, but pre-existing cognitive impairment is a predisposing factor. Here we explore the associations between delirium and cerebrospinal fluid (CSF) levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), proteins with important roles in both acute injury and chronic neurodegeneration. METHODS: Using a 13-plex Discovery Assay®, we quantified CSF levels of 9 MMPs and 4 TIMPs in 280 hip fracture patients (140 with delirium), 107 cognitively unimpaired individuals, and 111 patients with Alzheimer's disease dementia. The two delirium-free control groups without acute trauma were included to unravel the effects of acute trauma (hip fracture), dementia, and delirium. RESULTS: Here we show that delirium is associated with higher levels of MMP-2, MMP-3, MMP-10, TIMP-1, and TIMP-2; a trend suggests lower levels of TIMP-4 are also associated with delirium. Most delirium patients had pre-existing dementia and low TIMP-4 is the only marker associated with delirium in adjusted analyses. MMP-2, MMP-12, and TIMP-1 levels are clearly higher in the hip fracture patients than in both control groups and several other MMP/TIMPs are impacted by acute trauma or dementia status. CONCLUSIONS: Several CSF MMP/TIMPs are significantly associated with delirium in hip fracture patients, but alterations in most of these MMP/TIMPs could likely be explained by acute trauma and/or pre-fracture dementia. Low levels of TIMP-4 appear to be directly associated with delirium, and the role of this marker in delirium pathophysiology should be further explored.
Delirium is a syndrome in which there are substantial changes in a person's ability to focus, understand, or pay attention to events. Delirium often occurs in response to sudden trauma and is more common in persons with pre-existing cognitive impairment. What happens in the brain during delirium is not well understood. To learn more, we have studied whether markers in the cerebrospinal fluid were altered in people with delirium compared to people without delirium. To understand differences specifically caused by delirium, we included two control groups without acute trauma, one with cognitively healthy participants and one with dementia patients. We found several markers altered in people with delirium, with most of the markers similarly altered in people with cognitive impairment due to dementia. One marker was directly linked to delirium and could potentially shed light on the brain processes that cause the syndrome.
RESUMO
Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) have been linked to age-related neurodegeneration and Alzheimer's disease (AD), but their role in normal aging is poorly understood. We used linear mixed models to determine if baseline or rate of yearly change in cerebrospinal fluid (CSF) levels of MMP-2; MMP-3; MMP-10; TIMP-123 (composite of TIMP-1, TIMP-2, and TIMP-3); or TIMP-4 predicted changes in bilateral entorhinal cortex thickness, hippocampal volume, or lateral ventricle volume in cognitively unimpaired individuals. We also assessed effects on the CSF AD biomarkers amyloid-ß42 and phosphorylated tau181. Low baseline levels of MMP-3 predicted larger ventricle volumes and more entorhinal cortex thinning. Increased CSF MMP-2 levels over time predicted more entorhinal thinning, hippocampal atrophy, and ventricular expansion, while increased TIMP-123 over time predicted ventricular expansion. No MMP/TIMPs predicted changes in CSF AD biomarkers. Notably, we show for the first time that longitudinal increases in MMP-2 and TIMP-123 levels may predict age-associated brain atrophy. In conclusion, MMPs and TIMPs may play a role in brain atrophy in cognitively unimpaired aging.
Assuntos
Doença de Alzheimer , Metaloproteinase 2 da Matriz , Humanos , Metaloproteinase 2 da Matriz/líquido cefalorraquidiano , Metaloproteinase 3 da Matriz , Doença de Alzheimer/patologia , Atrofia/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Biomarcadores/líquido cefalorraquidianoRESUMO
There is increasing evidence for vesicular release of glutamate from astrocytes. We have previously demonstrated existence of VGLUT1 on astrocytic synaptic-like microvesicles (SMLVs) in several brain regions indicating a role in astroglial glutamate release. As VGLUT3 is prominently expressed in non-neuronal cells, this prompted us to investigate whether VGLUT3 is also involved in astroglial release of glutamate. Confocal microscopic investigations revealed that astrocytes in the hippocampus and the frontal cortex, as well as Bergmann glia in the cerebellum were labeled for VGLUT3. Immunogold cytochemistry showed that VGLUT3 gold particles were located over SMLVs in perisynaptic astrocytic and Bergmann glial processes. The specificity of the VGLUT3 immunoreactivity was demonstrated by abolished VGLUT3 labeling in astroglia in VGLUT3 knock-out mice. Double immunogold labeling showed that astrocytic processes contained labeling for VGLUT3 and VGLUT1, but the antibodies labeled separate subpopulations of vesicles in the processes. The ratio of gold particle densities between glial processes and nerve terminals were higher for VGLUT3 than for VGLUT1, suggesting that VGLUT3 is particularly abundant in astrocytic processes. Thus, our data show that VGLUT3 localizes to a distinct set of SMLVs in perisynaptic astroglial processes and suggest that VGLUT3 is important for glutamate release from astrocytes.
Assuntos
Astrócitos/metabolismo , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Vesículas Sinápticas/metabolismo , Proteínas Vesiculares de Transporte de Glutamato/metabolismo , Animais , Astrócitos/citologia , Glutamato-Amônia Ligase/metabolismo , Masculino , Camundongos , Camundongos Knockout , Ratos , Ratos Wistar , Proteína Vesicular 1 de Transporte de Glutamato/metabolismoRESUMO
Activation of NMDA receptor requires two co-agonists, glutamate and glycine. Despite its intrinsic role in brain functions molecular mechanisms involved in glutamate replenishment and identification of the origin of glycine have eluded characterization. We have performed direct measurements of glycine flux by SN2 (Slc38a5; also known as SNAT5), executed extensive electrophysiological characterization as well as implemented ratiometric analyses to show that SN2 transport resembles SN1 in mechanism but differ in functional implications. We report that rat SN2 mediates electroneutral and bidirectional transport of glutamine and glycine at perisynaptic astroglial membranes. Sophisticated coupled and uncoupled movements of H(+) differentially associate with glutamine and glycine transport by SN2 and regulate pH(i) and the release mode of the transporter. Consequently, SN2 doubles as a transmitter precursor furnisher and a potential regulator of NMDA receptors.
Assuntos
Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Astrócitos/metabolismo , Glicina/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Astrócitos/citologia , Linhagem Celular , Membrana Celular/metabolismo , Células Cultivadas , Ácido Glutâmico/metabolismo , Glutamina/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Ratos , Ratos Wistar , Xenopus laevisRESUMO
BACKGROUND: Delirium is a common and serious complication in geriatric patients. The pathophysiology of delirium is not known. OBJECTIVE: The objective of the current study was to test the hypothesis that cerebrospinal fluid (CSF) levels of inflammatory markers at the time of spinal anesthesia for hip surgery are associated with delirium. METHODS: In total 133 hip fracture patients and 125 cognitively healthy controls undergoing elective surgery, together with 73 Alzheimer's disease (AD) dementia patients, were recruited at Oslo University Hospital and Diakonhjemmet Hospital, Oslo, Norway. Delirium was evaluated daily in hip fracture patients by the Confusion Assessment Method (CAM). Depression was evaluated by Cornell Scale for Depression in Dementia (CSDD). Tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1ß), and interleukin-8 (IL-8) levels were measured in CSF using a Mesoscale Discovery (MSD) immunoassay. RESULTS: Hip fracture patients had significantly higher IL-8 levels (pâ<â0.001) compared to cognitively healthy controls or patients with stable AD dementia. Furthermore, preoperative IL-8 levels were significantly higher (pâ=â0.013) in hip fracture patients who developed delirium (incident delirium) after surgery as compared to patients with no delirium. However, subgroup analyses showed that IL-8 levels were only significantly higher in delirium patients without dementia (pâ=â0.006). In contrast, depression subgroup analysis showed that IL-8 concentration was significantly higher (pâ=â0.002) in delirium patients with depression. Both TNF-α and IL-1ß were undetected in most patients. CONCLUSIONS: Our study suggests that IL-8 levels are associated with delirium onset and that underlying depression or dementia influences IL-8 levels.
Assuntos
Delírio/líquido cefalorraquidiano , Demência/líquido cefalorraquidiano , Interleucina-8/líquido cefalorraquidiano , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/psicologia , Anestesia , Biomarcadores/líquido cefalorraquidiano , Delírio/psicologia , Demência/psicologia , Depressão/líquido cefalorraquidiano , Depressão/complicações , Feminino , Voluntários Saudáveis , Fraturas do Quadril/complicações , Fraturas do Quadril/cirurgia , Humanos , Inflamação/líquido cefalorraquidiano , Interleucina-1beta/líquido cefalorraquidiano , Masculino , Testes de Estado Mental e Demência , Testes Neuropsicológicos , Escalas de Graduação Psiquiátrica , Fator de Necrose Tumoral alfa/líquido cefalorraquidianoRESUMO
GABA signaling is involved in a wide range of neuronal functions, such as synchronization of action potential firing, synaptic plasticity and neuronal development. Sustained GABA signaling requires efficient mechanisms for the replenishment of the neurotransmitter pool of GABA. The prevailing theory is that exocytotically released GABA may be transported into perisynaptic astroglia and converted to glutamine, which is then shuttled back to the neurons for resynthesis of GABA-i.e., the glutamate/GABA-glutamine (GGG) cycle. However, an unequivocal demonstration of astroglia-to-nerve terminal transport of glutamine and the contribution of astroglia-derived glutamine to neurotransmitter GABA synthesis is lacking. By genetic inactivation of the amino acid transporter Solute carrier 38 member a1 (Slc38a1)-which is enriched on parvalbumin+ GABAergic neurons-and by intraperitoneal injection of radiolabeled acetate (which is metabolized to glutamine in astroglial cells), we show that Slc38a1 mediates import of astroglia-derived glutamine into GABAergic neurons for synthesis of GABA. In brain slices, we demonstrate the role of Slc38a1 for the uptake of glutamine specifically into GABAergic nerve terminals for the synthesis of GABA depending on demand and glutamine supply. Thus, while leaving room for other pathways, our study demonstrates a key role of Slc38a1 for newly formed GABA, in harmony with the existence of a GGG cycle.
Assuntos
Sistema A de Transporte de Aminoácidos/metabolismo , Astrócitos/metabolismo , Interneurônios/metabolismo , Neurotransmissores/metabolismo , Ácido gama-Aminobutírico/biossíntese , Acetatos/metabolismo , Animais , Glutamina/metabolismo , Camundongos , Modelos Biológicos , Sinapses/metabolismoRESUMO
Amino acids are essential for cellular protein synthesis, growth, metabolism, signaling and in stress responses. Cell plasma membranes harbor specialized transporters accumulating amino acids to support a variety of cellular biochemical pathways. Several transporters for neutral amino acids have been characterized. However, Slc38a2 (also known as SA1, SAT2, ATA2, SNAT2) representing the classical transport system A activity stands in a unique position: Being a secondarily active transporter energized by the electrochemical gradient of Na+, it creates steep concentration gradients for amino acids such as glutamine: this may subsequently drive the accumulation of additional neutral amino acids through exchange via transport systems ASC and L. Slc38a2 is ubiquitously expressed, yet in a cell-specific manner. In this review, we show that Slc38a2 is regulated at the transcriptional and translational levels as well as by ions and proteins through direct interactions. We describe how Slc38a2 senses amino acid availability and passes this onto intracellular signaling pathways and how it regulates protein synthesis, cellular proliferation and apoptosis through the mechanistic (mammalian) target of rapamycin (mTOR) and general control nonderepressible 2 (GCN2) pathways. Furthermore, we review how this extensively regulated transporter contributes to cellular osmoadaptation and how it is regulated by endoplasmic reticulum stress and various hormonal stimuli to promote cellular metabolism, cellular signaling and cell survival. This article is part of the issue entitled 'Special Issue on Neurotransmitter Transporters'.
Assuntos
Sistema A de Transporte de Aminoácidos/genética , Sistema A de Transporte de Aminoácidos/metabolismo , Aminoácidos/metabolismo , Transdução de Sinais/genética , Animais , Regulação da Expressão Gênica , Humanos , Biossíntese de ProteínasRESUMO
PURPOSE: To assess novel differences in serum levels of glucose, lactate and amino acids in patients with normal-tension glaucoma (NTG) compared to age-matched controls, at baseline and in response to universal hypoxia. METHODS: Twelve patients diagnosed with NTG and eleven control subjects underwent normobaric hypoxia for 2 hr. Peripheral venous blood samples were taken at baseline, during hypoxia and in the recovery phase. Serum glucose and lactate levels were measured by a blood gas analyser. Amino acids were analysed by high-performance liquid chromatography. RESULTS: Baseline levels of lactate and total amino acids were significantly lower in patients with NTG compared to healthy controls. No differences were seen in blood glucose levels between the two groups. Lactate levels remained unchanged during hypoxia in the control group, but increased in patients with NTG. In the recovery phase, total amino acid levels were reduced in the control group, whereas no changes were found in patients with NTG. CONCLUSION: Reduced serum levels of lactate and total amino acids were identified as potential markers for NTG. Moreover, significant differential regulatory patterns of certain amino acids were found in patients with NTG compared to control subjects. Overall, our results suggest a link between systemic energy metabolites and NTG and support a novel understanding of glaucoma as an inner retinal manifestation of a systemic condition.
Assuntos
Aminoácidos/sangue , Glicemia/metabolismo , Glaucoma/sangue , Hipóxia/sangue , Pressão Intraocular/fisiologia , Ácido Láctico/sangue , Idoso , Biomarcadores/sangue , Cromatografia Líquida de Alta Pressão , Feminino , Glaucoma/complicações , Glaucoma/fisiopatologia , Humanos , Hipóxia/complicações , Masculino , Estudos RetrospectivosRESUMO
The reorganizations of the overall intrinsic glutamatergic and gamma-aminobutyric acid (GABA)-ergic hippocampal networks as well as the time course of these reorganizations during development of pilocarpine-induced temporal lobe epilepsy were studied with in situ hybridization and immunohistochemistry experiments for the vesicular glutamate transporter 1 (VGLUT1) and the vesicular GABA transporter (VGAT). These transporters are particularly interesting as specific markers for glutamatergic and GABAergic neurons, respectively, whose expression levels could reflect the demand for synaptic transmission and their average activity. We report that 1) concomitantly with the loss of some subpopulations of VGAT-containing neurons, there was an up-regulation of VGAT synthesis in all remaining GABA neurons as early as 1 week after pilocarpine injection. This enhanced synthesis is characterized by marked increases in the relative amount of VGAT mRNAs in interneurons associated with increased intensity of axon terminal labeling for VGAT in all hippocampal layers. 2) There was a striking loss of mossy cells during the latent period, demonstrated by a long-term decrease of VGLUT1 mRNA-containing hilar neurons and associated loss of VGLUT1-containing terminals in the dentate gyrus inner molecular layer. 3) There were aberrant VGLUT1-containing terminals at the chronic stage resulting from axonal sprouting of granule and pyramidal cells. This is illustrated by a recovery of VGLUT1 immunoreactivity in the inner molecular layer and an increased VGLUT1 immunolabeling in the CA1-CA3 dendritic layers. These data indicate that an increased activity of remaining GABAergic interneurons occurs during the latent period, in parallel with the loss of vulnerable glutamatergic and GABAergic neurons preceding the reorganization of glutamatergic networks.
Assuntos
Hipocampo/metabolismo , Neurônios/metabolismo , Convulsões/metabolismo , Proteína Vesicular 1 de Transporte de Glutamato/metabolismo , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/metabolismo , Animais , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Hipocampo/citologia , Masculino , Vias Neurais/citologia , Vias Neurais/metabolismo , Neurônios/citologia , Pilocarpina , Ratos , Ratos Wistar , Convulsões/induzido quimicamente , Convulsões/patologiaRESUMO
[This corrects the article on p. 138 in vol. 4, PMID: 24106489.].
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BACKGROUND: The clinical relevance of brain ß-amyloidosis in older adults without dementia is not established. As delirium and dementia are strongly related, studies on patients with delirium may give pathophysiological clues. OBJECTIVE: To determine whether the Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers amyloid-ß 1-42 (Aß42), total tau (T-tau), and phosphorylated tau (P-tau) are associated with delirium in hip fracture patients with and without dementia. METHODS: CSF was collected in conjunction to spinal anesthesia in 129 patients. Delirium was assessed using the Confusion Assessment Method once daily in all patients, both pre- and postoperatively. The diagnosis of dementia at admission was based upon clinical consensus. CSF levels of Aß42, T-tau, and P-tau were analyzed. RESULTS: In patients without dementia, we found lower CSF Aß42 levels (median, 310âng/L versus 489âng/L, pâ=â0.006), higher T-tau levels (median, 505âng/L versus 351âng/L, pâ=â0.02), but no change in P-tau in patients who developed delirium (nâ=â16) compared to those who remained lucid (nâ=â49). Delirious patients also had lower ratios of Aß42 to T-tau (pâ<â0.001) and P-tau (pâ=â0.001) relative to those without delirium. CSF Aß42 and T-tau remained significantly associated with delirium status in adjusted analyses. In patients with dementia, CSF biomarker levels did not differ between those with (nâ=â54) and without delirium (nâ=â10). CONCLUSION: The reduction in CSF Aß42, indicating ß-amyloidosis, and increase in T-tau, indicating neurodegeneration, in hip fracture patients without dementia developing delirium indicates that preclinical AD brain pathology is clinically relevant and possibly plays a role in delirium pathophysiology.
Assuntos
Peptídeos beta-Amiloides/líquido cefalorraquidiano , Delírio/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/líquido cefalorraquidiano , Delírio/etiologia , Delírio/terapia , Demência/líquido cefalorraquidiano , Demência/complicações , Feminino , Fraturas do Quadril/líquido cefalorraquidiano , Fraturas do Quadril/complicações , Fraturas do Quadril/cirurgia , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fosforilação , Resultado do Tratamento , Proteínas tau/líquido cefalorraquidianoRESUMO
In mesial temporal lobe epilepsy (MTLE), spontaneous seizures likely originate from a multi-structural epileptogenic zone, including several regions of the limbic system connected to the hippocampal formation. In this study, we investigate the structural connectivity between the supramammillary nucleus (SuM) and the dentate gyrus (DG) in the model of MTLE induced by pilocarpine in the rat. This hypothalamic nucleus, which provides major extracortical projections to the hippocampal formation, plays a key role in the regulation of several hippocampus-dependent activities, including theta rhythms, memory function and emotional behavior, such as stress and anxiety, functions that are known to be altered in MTLE. Our findings demonstrate a marked reorganization of DG afferents originating from the SuM in pilocarpine-treated rats. This reorganization, which starts during the latent period, is massive when animals become epileptic and continue to evolve during epilepsy. It is characterized by an aberrant distribution and an increased number of axon terminals from neurons of both lateral and medial regions of the SuM, invading the entire inner molecular layer of the DG. This reorganization, which reflects an axon terminal sprouting from SuM neurons, could contribute to trigger spontaneous seizures within an altered hippocampal intrinsic circuitry.
Assuntos
Epilepsia do Lobo Temporal/patologia , Hipocampo/fisiopatologia , Hipotálamo Posterior/fisiopatologia , Terminações Pré-Sinápticas/patologia , Animais , Biotina/análogos & derivados , Biotina/metabolismo , Dextranos/metabolismo , Modelos Animais de Doenças , Epilepsia do Lobo Temporal/induzido quimicamente , Masculino , Agonistas Muscarínicos , Vias Neurais/fisiopatologia , Fosfopiruvato Hidratase/metabolismo , Pilocarpina/toxicidade , Vírus da Raiva/metabolismo , Ratos , Ratos Wistar , Proteína Vesicular 2 de Transporte de Glutamato/metabolismoRESUMO
Intercellular communication is pivotal in optimizing and synchronizing cellular responses to keep homeostasis and to respond adequately to external stimuli. In the central nervous system (CNS), glutamatergic and GABAergic signals are postulated to be dependent on the glutamate/GABA-glutamine cycle for vesicular loading of neurotransmitters, for inactivating the signal and for the replenishment of the neurotransmitters. Islets of Langerhans release the hormones insulin and glucagon, but share similarities with CNS cells in for example transcriptional control of development and differentiation, and chromatin methylation. Interestingly, CNS proteins involved in secretion of the neurotransmitters and emitting their responses as well as the regulation of these processes, are also found in islet cells. Moreover, high levels of glutamate, GABA, and glutamine and their respective vesicular and plasma membrane transporters have been shown in the islet cells and there is emerging support for these amino acids and their transporters playing important roles in the maturation and secretion of insulin and glucagon. In this review, we will discuss the feasibility of recent data in the field in relation to the biophysical properties of the transporters (Slc1, Slc17, Slc32, and Slc38) and physiology of hormone secretion in islets of Langerhans.