RESUMO
Overconsumption of high-fat diets (HFDs) can critically affect synaptic and cognitive functions within telencephalic structures such as the medial prefrontal cortex (mPFC). The underlying mechanisms, however, remain largely unknown. Here we show that adolescence is a sensitive period for the emergence of prefrontal cognitive deficits in response to HFD. We establish that the synaptic modulator reelin (RELN) is a critical mediator of this vulnerability because (1) periadolescent HFD (pHFD) selectively downregulates prefrontal RELN+ cells and (2) augmenting mPFC RELN levels using transgenesis or prefrontal pharmacology prevents the pHFD-induced prefrontal cognitive deficits. We further identify N-methyl-d-aspartate-dependent long-term depression (NMDA-LTD) at prefrontal excitatory synapses as a synaptic signature of this association because pHFD abolishes NMDA-LTD, a function that is restored by RELN overexpression. We believe this study provides the first mechanistic insight into the vulnerability of the adolescent mPFC towards nutritional stress, such as HFDs. Our findings have primary relevance to obese individuals who are at an increased risk of developing neurological cognitive comorbidities, and may extend to multiple neuropsychiatric and neurological disorders in which RELN deficiency is a common feature.
Assuntos
Moléculas de Adesão Celular Neuronais/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Córtex Pré-Frontal/crescimento & desenvolvimento , Córtex Pré-Frontal/metabolismo , Serina Endopeptidases/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Masculino , Desnutrição/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Plasticidade Neuronal , Receptores de N-Metil-D-Aspartato/metabolismo , Proteína Reelina , Sinapses/metabolismoRESUMO
Defective brain extracellular matrix (ECM) is a factor of vulnerability in various psychiatric diseases such as schizophrenia, depression and autism. The glycoprotein reelin is an essential building block of the brain ECM that modulates neuronal development and participates to the functions of adult central synapses. The reelin gene (RELN) is a strong candidate in psychiatric diseases of early onset, but its synaptic and behavioral functions in juvenile brain circuits remain unresolved. Here, we found that in juvenile reelin-haploinsufficient heterozygous reeler mice (HRM), abnormal fear memory erasure is concomitant to reduced dendritic spine density and anomalous long-term potentiation in the prefrontal cortex. In juvenile HRM, a single in vivo injection with ketamine or Ro25-6981 to inhibit GluN2B-N-methyl-D-aspartate receptors (NMDARs) restored normal spine density, synaptic plasticity and converted fear memory to an erasure-resilient state typical of adult rodents. The functional and behavioral rescue by ketamine was prevented by rapamycin, an inhibitor of the mammalian target of rapamycin pathway. Finally, we show that fear memory erasure persists until adolescence in HRM and that a single exposure to ketamine during the juvenile period reinstates normal fear memory in adolescent mice. Our results show that reelin is essential for successful structural, functional and behavioral development of juvenile prefrontal circuits and that this developmental period provides a critical window for therapeutic rehabilitation with GluN2B-NMDAR antagonists.
Assuntos
Moléculas de Adesão Celular Neuronais/genética , Proteínas da Matriz Extracelular/genética , Proteínas do Tecido Nervoso/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Serina Endopeptidases/genética , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Análise de Variância , Animais , Animais Recém-Nascidos , Moléculas de Adesão Celular Neuronais/deficiência , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/genética , Relação Dose-Resposta a Droga , Fármacos Atuantes sobre Aminoácidos Excitatórios/farmacologia , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Proteínas da Matriz Extracelular/deficiência , Medo/efeitos dos fármacos , Medo/fisiologia , Feminino , Técnicas In Vitro , Ketamina/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/deficiência , Técnicas de Patch-Clamp , Fenóis , Piperidinas/farmacologia , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/crescimento & desenvolvimento , Proteína Reelina , Serina Endopeptidases/deficiência , Transdução de Sinais/efeitos dos fármacos , SirolimoRESUMO
Coordinated signalling between presynaptic terminals and their postsynaptic targets is essential for the development and function of central synapses. In addition to diffusible molecules, this bidirectional flow of information could involve direct interactions through cell-adhesion molecules. Here, we show that one class of cell-adhesion molecule, the integrins, are required for the functional maturation of hippocampal synapses in vitro. At immature synapses, a high probability of glutamate release (Pr) was correlated with the expression of postsynaptic NMDA (N-methyl-D-aspartate) receptors containing the NR2B subunit. The activity-dependent reduction in Pr and a switch in the subunit composition of synaptic NMDA receptors was prevented by chronic blockade with peptides containing the integrin-binding site Arg-Gly-Asp (RGD), or by a functional antibody against the beta3 integrin subunit. Active synapses, monitored by the uptake of antibodies against the intraluminal domain of synaptotagmin I, also had beta3 subunit immunoreactivity. Our results provide evidence that integrin-mediated signalling is essential for the orchestrated maturation of central excitatory synapses.
Assuntos
Proteínas de Ligação ao Cálcio , Hipocampo/citologia , Hipocampo/metabolismo , Integrinas/metabolismo , Terminações Pré-Sinápticas/metabolismo , Sinapses/metabolismo , Animais , Antígenos CD/metabolismo , Adesão Celular/efeitos dos fármacos , Células Cultivadas , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Genisteína/farmacologia , Ácido Glutâmico/metabolismo , Integrina beta3 , Integrinas/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intercelular , Isoflavonas/farmacologia , Glicoproteínas de Membrana/metabolismo , Modelos Neurológicos , Proteínas do Tecido Nervoso/metabolismo , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Oligopeptídeos/metabolismo , Oligopeptídeos/farmacologia , Peptídeos/farmacologia , Glicoproteínas da Membrana de Plaquetas/antagonistas & inibidores , Glicoproteínas da Membrana de Plaquetas/metabolismo , Terminações Pré-Sinápticas/efeitos dos fármacos , Subunidades Proteicas , Quinazolinas , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/química , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Sinaptotagmina I , Sinaptotagminas , Tirfostinas/farmacologiaRESUMO
Metabotropic glutamate receptors (mGluRs) can increase intracellular Ca2+ concentration via Ins(1,4,5)P3- and ryanodine-sensitive Ca2+ stores in neurons. Both types of store are coupled functionally to Ca2+-permeable channels found in the plasma membrane. The mGluR-mediated increase in intracellular Ca2+ concentration can activate Ca2+-sensitive K+ channels and Ca2+-dependent nonselective cationic channels. These mGluR-mediated effects often result from mobilization of Ca2+ from ryanodine-sensitive, rather than Ins(1,4, 5)P3-sensitive, Ca2+ stores, suggesting that close functional interactions exist between mGluRs, intracellular Ca2+ stores and Ca2+-sensitive ion channels in the membrane.
Assuntos
Cálcio/metabolismo , Canais Iônicos/metabolismo , Neurônios/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Animais , Canais de Cálcio/metabolismo , Proteínas de Transporte/química , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Proteínas de Arcabouço Homer , Humanos , Plasticidade Neuronal , Neuropeptídeos/química , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Canais de Potássio/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismoRESUMO
BACKGROUND: Optic disc elevation associated with Down syndrome is an uncommon phenomenon and raises the suspicion of an intracranial space-occupying lesion, thus necessitating the consideration of invasive and noninvasive investigations. METHOD OF STUDY: Four patients with Down syndrome and optic disc elevation without an underlying intracranial pathology are reported. Thorough ophthalmological and neuroradiological investigations were performed on each patient. Mild hyperopia occurred in three patients and myopia in one. CONCLUSIONS: We believe that in most Down syndrome patients with disc elevation, fluorescein angiography and/or clinical follow-up may be sufficient.
Assuntos
Síndrome de Down/patologia , Disco Óptico/patologia , Criança , Pré-Escolar , Feminino , Angiofluoresceinografia , Fundo de Olho , Humanos , Pressão Intracraniana , MasculinoRESUMO
As metabotropic glutamate receptor type 1 (mGluR1) is known to couple L-type Ca2+ channels and ryanodine receptors (RyR, Chavis et al., 1996) in cerebellar granule cells, we examined if such a coupling could activate a Ca2+-sensitive K+ channel, the big K+ (BK) channel, in cultured cerebellar granule cells. We observed that (+/-)-1-amino-cyclopentane-trans-1,3-dicarboxylic acid (t-ACPD) and quisqualate (QA) stimulated the activity of BK channels. On the other hand, (2S, 3S, 4S)-alpha-carboxycyclopropyl-glycine (L-CCG-I) and L-(+)-2-amino-4-phosphonobutyrate (L-AP4) had no effect on BK channels, indicating a specific activation by group I mGluRs. Group I mGluRs stimulation of the basal BK channel activity was mimicked by caffeine and both effects were blocked by ryanodine and nifedipine. Interestingly, carbachol stimulated BK channel activity but through a pertussis toxin (PTX)-sensitive pathway that was independent of L-type Ca2+ channel activity. Our report indicates that unlike the muscarinic receptors, group I mGluRs activate BK channels by mobilizing an additional pathway involving RyR and L-type Ca2+ channels.
Assuntos
Canais de Cálcio/fisiologia , Neurônios/metabolismo , Canais de Potássio/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/fisiologia , Animais , Canais de Cálcio Tipo L , Masculino , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Canais de Potássio/agonistas , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/fisiologia , Receptores Muscarínicos/fisiologiaRESUMO
OBJECTIVE: This study aimed to determine whether heparin surface-modified (HSM) intraocular lenses (IOLs) with a hydrophilic surface would reduce cell adherence and other postoperative changes compared with the conventional polymethylmethacrylate (PMMA) IOLs in patients with either diabetes mellitus or inactive uveitis. DESIGN: The study design was a randomized, double-masked, clinical trial. PARTICIPANTS: Twenty-five patients with bilateral cataracts, 14 with inactive anterior uveitis and 11 with diabetes, with an age range of 11 to 81 years (mean, 52.8 years) participated. INTERVENTION: Bilateral cataract extraction with posterior chamber IOL implantation was measured, each patient receiving an HSM lens in one eye and a PMMA lens in the other. Pharmacia one-piece HSM and PMMA IOLs were used. Postoperative ocular changes were evaluated at regular intervals for 24 months in patients with inactive uveitis and for 6 months in patients with diabetes. Patients and physicians alike were unaware of which eye contained which lens until postoperative results were compiled. Records were kept by a study coordinator. MAIN OUTCOME MEASURES: Comparisons of posterior synechiae, IOL cellular deposits, and posterior capsular fibrosis between PMMA and HSM IOLs were measured. RESULTS: Using the chi-square test, no statistically significant difference was found between the HSM and PMMA IOLs in the number of cellular deposits found on the anterior IOL surface, the number of adhesions between the iris and IOL, or the incidence of capsular opacification. CONCLUSION: The HSM and PMMA IOLs showed similar postoperative results in patients with inactive uveitis or diabetes mellitus.
Assuntos
Diabetes Mellitus Tipo 2/cirurgia , Heparina , Implante de Lente Intraocular , Lentes Intraoculares , Uveíte Anterior/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Catarata/patologia , Catarata/prevenção & controle , Extração de Catarata , Adesão Celular , Criança , Método Duplo-Cego , Feminino , Fibrose/prevenção & controle , Humanos , Doenças da Íris/prevenção & controle , Cápsula do Cristalino/patologia , Masculino , Pessoa de Meia-Idade , Polimetil Metacrilato , Estudos Prospectivos , Aderências Teciduais/prevenção & controleRESUMO
Adenylyl cyclase (AC) modulation of vesicular cycling was visualized at cultured cerebellar granule cell synapses using the sequential uptake of antibodies directed against the intraluminal domain of synaptotagmin I. Vesicle recycling due to spontaneous transmitter release in the absence of action potentials was increased by the AC/protein kinase A (PKA) activators forskolin and CPT-cAMP. These effects were blocked by the PKA inhibitor Rp-cAMPs. Cyclic AMP elevation also induced new cycling at previously silent sites. Activation of L-AP4-sensitive mGluR reduced the cAMP/PKA enhancement at preexisting synapses downstream of both AC and calcium channels. Modulation of the turnover and the number of vesicular release sites provide one mechanism that may underlie cAMP-dependent cerebellar long-term potentiation.
Assuntos
Cerebelo/fisiologia , AMP Cíclico/fisiologia , Neurônios/fisiologia , Sinapses/fisiologia , Potenciais de Ação , Adenilil Ciclases/metabolismo , Aminobutiratos/farmacologia , Animais , Anticorpos , Proteínas de Ligação ao Cálcio/fisiologia , Células Cultivadas , Cerebelo/citologia , Colforsina/farmacologia , AMP Cíclico/análogos & derivados , AMP Cíclico/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Ativação Enzimática , Antagonistas de Aminoácidos Excitatórios/farmacologia , Técnica Indireta de Fluorescência para Anticorpo , Masculino , Glicoproteínas de Membrana/imunologia , Glicoproteínas de Membrana/fisiologia , Camundongos , Proteínas do Tecido Nervoso/imunologia , Proteínas do Tecido Nervoso/fisiologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Sinaptotagmina I , Sinaptotagminas , Tionucleotídeos/farmacologiaAssuntos
Herpes Simples/virologia , Uveíte Anterior/virologia , Segmento Anterior do Olho/virologia , Antivirais/administração & dosagem , Antivirais/uso terapêutico , Diagnóstico Diferencial , Glucocorticoides/administração & dosagem , Glucocorticoides/uso terapêutico , Herpes Simples/diagnóstico , Herpes Simples/tratamento farmacológico , Humanos , Simplexvirus/genética , Simplexvirus/imunologia , Simplexvirus/isolamento & purificação , Uveíte Anterior/diagnóstico , Uveíte Anterior/tratamento farmacológicoRESUMO
PURPOSE: To study the course and visual outcome of Vogt-Koyanagi-Harada (VKH) syndrome in children. METHODS: The medical records of 97 consecutive patients with VKH syndrome were reviewed. Patients had been seen at King Khaled Eye Specialist Hospital in Riyadh, Saudi Arabia. The records were divided into two groups: those in whom the onset of the disease occurred at the age of 14 years or younger (pediatric group) and those in whom the disease manifested after the age of 14 years (adult group). RESULTS: Eight (61%) of the 13 children required cataract surgery compared to 14(17%) of 84 adult patients. Despite medical and surgical therapy, eight (61%) of the pediatric group had a final visual acuity of 20/200 or worse compared with 22 (26%) of the 84 adult patients (p=0.0103). CONCLUSION: The course of early-onset VKH (before the age of 14 years) appears to be aggressive. The ocular complications are more severe in children than in adults, leading to rapid deterioration in vision. Despite therapy, the final visual outcome of VKH in children is poor.
Assuntos
Síndrome Uveomeningoencefálica/complicações , Adolescente , Adulto , Extração de Catarata , Criança , Pré-Escolar , Oftalmopatias/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome Uveomeningoencefálica/fisiopatologia , Síndrome Uveomeningoencefálica/terapia , Transtornos da Visão/etiologia , Acuidade VisualRESUMO
A 39 year-old Behcet's patient had demyelination of retinal myelinated nerve fibers after recurrent papillitis and vitritis. Oral Prednisolone, cyclosporine, and later periocular corticosteroids and oral colchicine were used but demyelination continued over a 5 year-period. A pseudobulbar palsy with urinary incontinence and pyramidal tract signs developed and azathioprine and corticosteroids were used. Demyelination of retinal nerve fibers stopped and while treatment was underway, the central nervous system (CNS) signs were stable. While the ocular pathology of Behcet's can mirror the CNS signs, indeed optic nerve ischemic demyelination may signal the potential for CNS involvement; azathioprine with prednisone may be more effective in the long-term for optic nerve and CNS involvement than cyclosporine with prednisone.
Assuntos
Síndrome de Behçet/complicações , Doenças Desmielinizantes/etiologia , Fibras Nervosas Mielinizadas , Doenças Retinianas/etiologia , Adulto , Síndrome de Behçet/tratamento farmacológico , Colchicina/administração & dosagem , Colchicina/uso terapêutico , Doenças Desmielinizantes/tratamento farmacológico , Doenças Desmielinizantes/patologia , Seguimentos , Fundo de Olho , Glucocorticoides/administração & dosagem , Glucocorticoides/uso terapêutico , Supressores da Gota/administração & dosagem , Supressores da Gota/uso terapêutico , Humanos , Injeções , Masculino , Doenças Retinianas/tratamento farmacológico , Doenças Retinianas/patologiaRESUMO
BACKGROUND: A young woman with a history of controlled hypertension noted a suddenly decreased peripheral temporal field in the left eye. This occurred after moderate peripartum hypertension. METHOD: A monocular peripheral temporal crescentic defect could be plotted on Goldmann visual fields despite a normal dilated peripheral retinal examination and normal disc appearance. RESULT: A dilated parieto-occipital sulcus could be seen on computed tomography, and magnetic resonance imaging showed changes consistent with atrophy and gliosis in the cuneus, precuneus, and anterior calcarine cortex surrounding the parieto-occipital sulcus. CONCLUSION: By magnetic resonance imaging, this can be seen to comprise less than 10% of the visual cortex, as suggested by the Horton and Hoyt revised Holmes map. The temporal crescent syndrome is a rare monocular retrochiasmatic visual field defect that can be correlated to a lesion along the parieto-occipital sulcus.
Assuntos
Encefalopatias/diagnóstico , Encéfalo/patologia , Hemianopsia/etiologia , Campos Visuais , Adulto , Pressão Sanguínea , Encefalopatias/complicações , Feminino , Humanos , Hipertensão/complicações , Imageamento por Ressonância Magnética , Síndrome , Acuidade VisualRESUMO
AIMS/BACKGROUND: To assess the outcome and complications of cataract extraction in patients with Behçet's disease. METHODS: Thirty-six Behçet's disease patients underwent cataract surgery without intraocular lens implantation. Twenty-six patients had phacoemulsification or extracapsular cataract extraction, and ten patients had pars plana lensectomy/vitrectomy. The follow-up period ranged from 24 to 84 months (mean, 38 months). RESULTS: There was no statistically significant difference in the follow-up period of patients who underwent phacoemulsification, extracapsular cataract extraction, or pars plana lensectomy/vitrectomy. Sixteen (62%) of 26 patients who had extracapsular cataract extraction or phacoemulsification had a visual acuity of 20/200 or better compared with none of the 10 patients who had pars plana lensectomy/vitrectomy. Three (30%) of ten eyes which underwent pars plana lensectomy/vitrectomy eventuated in phthisis bulbi while none of the eyes that underwent extracapsular cataract extraction or phacoemulsification developed phthisis bulbi. CONCLUSION: Extracapsular cataract extraction or phacoemulsification had a better visual outcome and fewer postoperative complications than pars plana lensectomy/vitrectomy in patients with Behçet's disease.
Assuntos
Síndrome de Behçet/complicações , Extração de Catarata , Adulto , Idoso , Feminino , Seguimentos , Humanos , Lentes Intraoculares , Masculino , Pessoa de Meia-Idade , Facoemulsificação , Complicações Pós-Operatórias , Resultado do Tratamento , Acuidade Visual , VitrectomiaRESUMO
In skeletal muscle, L-type Ca2+ channels act as voltage sensors to control ryanodine-sensitive Ca2+ channels in the sarcoplasmic reticulum. It has recently been demonstrated that these ryanodine receptors generate a retrograde signal that modifies L-type Ca2+ -channel activity. Here we demonstrate a tight functional coupling between ryanodine receptors and L-type Ca2+ channel in neurons. In cerebellar granule cells, activation of the type-1 metabotropic glutamate receptor (mGluR1) induced a large, oscillating increase of the L-type Ba2+ current. Activation occurred independently of inositol 1,4,5-trisphosphate and classical protein kinases, but was mimicked by caffeine and blocked by ryanodine. The kinetics of this blockade were dependent on the frequency of Ba2+ current stimulation. Both mGluR1 and caffeine-induced increase in L-type Ca2+ -channel activity persisted in inside-out membrane patches. In these excised patches, ryanodine suppressed both the mGluR1- and caffeine-activated L-type Ca2+ channels. These results demonstrate a novel mechanism for Ca2+ -channel modulation in neurons.
Assuntos
Canais de Cálcio/metabolismo , Proteínas Musculares/metabolismo , Neurônios/metabolismo , Animais , Bário/metabolismo , Cafeína/farmacologia , Canais de Cálcio/efeitos dos fármacos , Células Cultivadas , Cerebelo/citologia , Cicloleucina/análogos & derivados , Cicloleucina/farmacologia , Inositol 1,4,5-Trifosfato/metabolismo , Potenciais da Membrana , Camundongos , Proteínas Musculares/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Proteínas Quinases/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Rianodina/farmacologia , Canal de Liberação de Cálcio do Receptor de Rianodina , Fosfolipases Tipo C/metabolismoAssuntos
Doenças Orbitárias/diagnóstico , Tuberculose Ocular/diagnóstico , Adolescente , Anti-Inflamatórios/uso terapêutico , Antituberculosos/uso terapêutico , Diagnóstico Diferencial , Feminino , Humanos , Linfonodos/patologia , Infecções por Mycobacterium/diagnóstico , Infecções por Mycobacterium/tratamento farmacológico , Órbita/patologia , Doenças Orbitárias/tratamento farmacológico , Esteroides , Tomografia Computadorizada por Raios X , Teste Tuberculínico , Tuberculose Meníngea/diagnóstico , Tuberculose Meníngea/tratamento farmacológico , Tuberculose Ocular/tratamento farmacológicoRESUMO
Three children from consanguineous parents began losing the ability to walk in late infancy. Despite chronically progressive weakness leading to wheelchair dependence by adolescence and later loss of motor speech production, intellect remained preserved. Examination revealed upper motor neuron findings of pseudobulbar palsy and spastic quadriplegia, without dementia, cerebellar, extrapyramidal or sensory signs. In addition they exhibited a diffuse conjugate saccadic gaze paresis, especially severe on down-gaze. CT and MRI scans of brain and spinal cord, EEGs, visual and brainstem auditory evoked potentials, CSF examinations, enzyme assays for lysosomal storage diseases, blood amino acids and urine organic acids were all normal. Cortical somatosensory evoked potentials were poorly configured in two of the patients, though they had normal central conduction. EMG showed no signs of denervation. Nerve conduction studies showed normal peripheral motor and sensory conduction velocities. Transcranial magnetic stimulation of the brain elicited no motor-evoked potentials. Despite the lack of neuropathological confirmation, the clinical course and neurophysiologic data strongly support the diagnosis of a familial (autosomal recessive) primary lateral sclerosis (PLS).
Assuntos
Esclerose Lateral Amiotrófica/complicações , Esclerose Lateral Amiotrófica/genética , Transtornos da Motilidade Ocular/complicações , Paresia/complicações , Adolescente , Esclerose Lateral Amiotrófica/fisiopatologia , Consanguinidade , Eletroencefalografia , Eletromiografia , Potenciais Somatossensoriais Evocados , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Nervo Mediano/fisiopatologia , Nistagmo Optocinético , Transtornos da Motilidade Ocular/diagnóstico , Nervo Tibial/fisiopatologia , Tomografia Computadorizada por Raios XRESUMO
We investigated the mechanisms by which metabotropic glutamate receptors (mGluRs) modulate specific Ca2+ channels in cerebellar granule cells. A large fraction of the current in granule cells is carried by L- and Q-type Ca2+ channels (about 26% each), whereas N- and P-type contribute proportionally less to the global current (9 and 15%, respectively). l-Aminocyclopentane-dicarboxylate (t-ACPD), (2S,3S,4S)-alpha-(carboxycyclopropyl)-glycine (L-CCGI) and (S)-4-carboxy-3-hydroxyphenylglycine [(S)-4C3HPG], but not L(+)-2-amino-4-phosphonobutyrate (L-AP4) reduced the Ca2+ current amplitude. The t-ACPD-induced inhibition was fully antagonized by (+/-)-methyl-4-carboxyphenylglycine [(+/-)-MCPG] and blocked by pertussis toxin (PTX). These results are consistent with inhibitory response mediated by mGluR2/R3. The use of specific Ca2+ channel blockers provided evidence that mGluR2/R3 inhibited both L- and N-type Ca2+ currents. In PTX-treated cells, Glu or t-ACPD, but not L-CCGI or L-AP4, increased the Ca2+ current. Consistent with the activation of mGluR1, the antagonists (+)-MCPG and (S)-4C3HPG prevented the facilitation of Ca2+ current produced by t-ACPD. The mGluR1-activated facilitation was completely blocked by nimodipine, indicating that L-type Ca2+ currents were selectively potentiated.
Assuntos
Canais de Cálcio/metabolismo , Cerebelo/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Cerebelo/citologia , Cerebelo/efeitos dos fármacos , Técnicas de Cultura , Eletrofisiologia , Masculino , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Técnicas de Patch-Clamp , Toxina Pertussis , Receptores de Glutamato Metabotrópico/agonistas , Fatores de Virulência de Bordetella/farmacologiaAssuntos
Síndrome de Behçet/epidemiologia , Adolescente , Adulto , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/genética , Síndrome de Behçet/terapia , Vasos Sanguíneos/patologia , Criança , Oftalmopatias/diagnóstico , Oftalmopatias/etiologia , Oftalmopatias/terapia , Feminino , Gastroenteropatias/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/etiologia , Pele/patologia , Acuidade VisualRESUMO
The effect of metabotropic glutamate receptor activation on Ca dihydropyridine (DHP)-sensitive channels recorded in the presence of 1 microM Bay K 8644 was examined on cultured cerebellar granule cells using the patch-clamp technique in the cell-attached configuration. Bath-applied agonist (trans-ACPD, 1S,3R-, and 1R,3S-ACPD isomers, and glutamate or quisqualate in the presence of CPP and CNQX) evoked an increase in Ca channel activity with a variable latency of 8.9 +/- 8.6 sec in 40% of the recorded cells. Neither L-CCG1, L-AP3, L-AP4, nor AMPA or NMDA activated Ca channels. Two dihydropyridine-sensitive channels present in this cell type were activated by trans-ACPD: the classical 24 pS L-type channel and a smaller-conductance 7 pS channel. The effect was shown to be mediated by neither intracellular Ca2+ nor a pertussis toxin (PTX)-sensitive G protein. Interestingly treatment with BAPTA-AM increased the number of responding patches and the activity was more sustained throughout the drug application. After overnight PTX treatment, activation of the Ca channels persisted even after washout of the agonist. These results indicate that mGluR1/mGluR5 probably mediate the facilitation of dihydropyridine-sensitive Ca channels.