RESUMO
The information from nociceptors is processed in the dorsal horn of the spinal cord by complex circuits involving excitatory and inhibitory interneurons. It is well documented that GluN2B and ERK1/2 phosphorylation contributes to central sensitization. Striatal-enriched protein tyrosine phosphatase (STEP) dephosphorylates GluN2B and ERK1/2, promoting internalization of GluN2B and inactivation of ERK1/2. The activity of STEP was modulated by genetic (STEP knockout mice) and pharmacological (recently synthesized STEP inhibitor, TC-2153) approaches. STEP(61) protein levels in the lumbar spinal cord were determined in male and female mice of different ages. Inflammatory pain was induced by complete Freund's adjuvant injection. Behavioral tests, immunoblotting, and electrophysiology were used to analyze the effect of STEP on nociception. Our results show that both genetic deletion and pharmacological inhibition of STEP induced thermal hyperalgesia and mechanical allodynia, which were accompanied by increased pGluN2B(Tyr1472) and pERK1/2(Thr202/Tyr204)levels in the lumbar spinal cord. Striatal-enriched protein tyrosine phosphatase heterozygous and knockout mice presented a similar phenotype. Furthermore, electrophysiological experiments showed that TC-2153 increased C fiber-evoked spinal field potentials. Interestingly, we found that STEP(61) protein levels in the lumbar spinal cord inversely correlated with thermal hyperalgesia associated with age and female gender in mice. Consistently, STEP knockout mice failed to show age-related thermal hyperalgesia, although gender-related differences were preserved. Moreover, in a model of inflammatory pain, hyperalgesia was associated with increased phosphorylation-mediated STEP(61) inactivation and increased pGluN2B(Tyr1472) and pERK1/2(Thr202/Tyr204)levels in the lumbar spinal cord. Collectively, the present results underscore an important role of spinal STEP activity in the modulation of nociception.
Assuntos
Nociceptividade/fisiologia , Limiar da Dor/efeitos dos fármacos , Dor/patologia , Dor/fisiopatologia , Proteínas Tirosina Fosfatases não Receptoras/deficiência , Animais , Benzotiepinas/farmacologia , Benzotiepinas/uso terapêutico , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Potenciais Evocados/efeitos dos fármacos , Potenciais Evocados/genética , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Hiperalgesia/tratamento farmacológico , Hiperalgesia/genética , Hiperalgesia/metabolismo , Hiperalgesia/patologia , Inflamação/induzido quimicamente , Inflamação/complicações , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fibras Nervosas Amielínicas/efeitos dos fármacos , Fibras Nervosas Amielínicas/fisiologia , Nociceptividade/efeitos dos fármacos , Dor/etiologia , Proteínas Tirosina Fosfatases não Receptoras/genética , Ratos , Ratos Sprague-Dawley , Transdução de SinaisRESUMO
The molecular and physiological basis of the touch-unresponsive zebrafish mutant fakir has remained elusive. Here we report that the fakir phenotype is caused by a missense mutation in the gene encoding voltage-gated calcium channel 2.1b (CACNA1Ab). Injection of RNA encoding wild-type CaV2.1 restores touch responsiveness in fakir mutants, whereas knockdown of CACNA1Ab via morpholino oligonucleotides recapitulates the fakir mutant phenotype. Fakir mutants display normal current-evoked synaptic communication at the neuromuscular junction but have attenuated touch-evoked activation of motor neurons. NMDA-evoked fictive swimming is not affected by the loss of CaV2.1b, suggesting that this channel is not required for motor pattern generation. These results, coupled with the expression of CACNA1Ab by sensory neurons, suggest that CaV2.1b channel activity is necessary for touch-evoked activation of the locomotor network in zebrafish.
Assuntos
Canais de Cálcio Tipo N/metabolismo , Ativação do Canal Iônico/genética , Tato/genética , Acetilcolina/farmacologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/genética , Vias Aferentes/fisiologia , Animais , Animais Geneticamente Modificados , Bungarotoxinas/metabolismo , Canais de Cálcio Tipo N/genética , Curare/farmacologia , Relação Dose-Resposta a Droga , Embrião não Mamífero , Reação de Fuga/efeitos dos fármacos , Reação de Fuga/fisiologia , Potenciais Evocados/genética , Células HEK293 , Humanos , Ativação do Canal Iônico/efeitos dos fármacos , Leucina/genética , Locomoção/efeitos dos fármacos , Locomoção/genética , Modelos Moleculares , Morfolinas/farmacologia , Atividade Motora/genética , Neurônios Motores/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiologia , Mutagênese Sítio-Dirigida/métodos , Mutação/genética , Mutação de Sentido Incorreto/genética , Rede Nervosa/fisiologia , Antagonistas Nicotínicos/farmacologia , Medula Espinal/citologia , Medula Espinal/fisiologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/genética , Tato/fisiologia , Valina/genética , Peixe-Zebra , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismoRESUMO
It is proposed an historical approach to concepts leading to the development of operational paradigms for measuring objectives neurophysiological endophenotypes. It is hypothesized that psychiatric interest for paradigms measuring Event-Related Potential (ERP) come from Bleuler (1911) and McGhie and Chapman (1961) phenomenological and clinical descriptions. They noted, first that patients with schizophrenia generally feel as if they are being flooded by an overwhelming mass of sensory input combined with a heightened sensory perception, second that they were distractible to irrelevant sensory stimuli. These subjective abnormalities may be related, first to inability to filter incongruent information measured in a double click paradigm by a deficit in P50 amplitude gating, and second to an inability to select a stimulus of interest measured in the oddball paradigm by a deficit in P300 amplitude. The analysis of these P50 and P300 ERP in cohorts of patients with schizophrenia found most of Gottesman endophenotype criteria. P50 and P300 ERP are therefore relevant neurophysiological endophenotypes. However, from a clinical point of view, these endophenotypes lack specificity. The hypothesis of this article leads us to formulate ways of research. It is shown the value of combining objective neurophysiological measures with subjective measures using self-administered questionnaires ("offline") or psychophysiological tests ("online") to develop rigorous neurophysiological experimental paradigms especially as clinical observations of their origins are not forgotten.
Assuntos
Nível de Alerta/genética , Nível de Alerta/fisiologia , Encéfalo/fisiopatologia , Endofenótipos , Potenciais Evocados/genética , Potenciais Evocados/fisiologia , Esquizofrenia/genética , Esquizofrenia/fisiopatologia , Psicologia do Esquizofrênico , Filtro Sensorial/genética , Filtro Sensorial/fisiologia , Estimulação Acústica , Atenção/fisiologia , Potenciais Evocados P300/genética , Potenciais Evocados P300/fisiologia , Predisposição Genética para Doença/genética , Humanos , Esquizofrenia/diagnósticoRESUMO
Neural inhibition within the thalamus is integral in shaping thalamocortical oscillatory activity. Fast, synaptic inhibition is primarily mediated by activation of heteropentameric GABA(A) receptor complexes. Here, we examined the synaptic physiology and network properties of mice lacking GABA(A) receptor alpha3, a subunit that in thalamus is uniquely expressed by inhibitory neurons of the reticular nucleus (nRT). Deletion of this subunit produced a powerful compensatory gain in inhibitory postsynaptic response in nRT neurons. Although, other forms of inhibitory and excitatory synaptic transmission in the circuit were unchanged, evoked thalamic oscillations were strongly dampened in alpha3 knockout mice. Furthermore, pharmacologically induced thalamocortical absence seizures displayed a reduction in length and power in alpha3 knockout mice. These studies highlight the role of GABAergic inhibitory strength within nRT in the maintenance of thalamic oscillations, and demonstrate that inhibitory intra-nRT synapses are a critical control point for regulating higher order thalamocortical network activity.
Assuntos
Epilepsia Tipo Ausência/fisiopatologia , Receptores de GABA-A/fisiologia , Sinapses/fisiologia , Tálamo/fisiologia , Animais , Potenciais Evocados/genética , Deleção de Genes , Núcleos Intralaminares do Tálamo/fisiologia , Camundongos , Camundongos Knockout , Receptores de GABA-A/genética , Transmissão SinápticaAssuntos
Nível de Alerta/fisiologia , Transtornos Cronobiológicos/fisiopatologia , Epilepsia do Lobo Frontal/fisiopatologia , Adolescente , Transtornos Cronobiológicos/genética , Sincronização Cortical , Eletroencefalografia/métodos , Epilepsia do Lobo Frontal/diagnóstico , Epilepsia do Lobo Frontal/genética , Potenciais Evocados/genética , Feminino , Lobo Frontal/fisiopatologia , Predisposição Genética para Doença/genética , Humanos , Mutação/genética , Valor Preditivo dos Testes , Receptores Nicotínicos/genética , Convulsões/diagnóstico , Convulsões/genética , Convulsões/fisiopatologia , Sono/fisiologia , Tálamo/fisiopatologiaRESUMO
OBJECTIVE: Several components of event-related potentials--P50 suppression, P300 amplitude and latency, and mismatch negativity--have been proposed as potential endophenotypes for schizophrenia on the basis of family studies. The present study used a twin design to estimate the extent of genetic overlap between these indices and the liability to schizophrenia. METHOD: The authors measured mismatch negativity, P300, and P50 suppression in 16 monozygotic twin pairs concordant for schizophrenia, nine monozygotic twin pairs discordant for schizophrenia, and 78 healthy comparison twin pairs. The study design was based on a power calculation. Structural equation modeling was used to quantify the genetic and environmental contributions to the phenotypic covariance between schizophrenia and each of the event-related potential indices. RESULTS: Significant phenotypic correlation with schizophrenia was found for each of the event-related potential components. Genetic factors were the main source of the phenotypic correlations. P50 suppression had the greatest genetic correlation with schizophrenia, followed by P300 amplitude, P300 latency, and mismatch negativity. CONCLUSIONS: All four event-related potential indices are potentially valid endophenotypes for schizophrenia, but P50 suppression and P300 amplitude show the closest genetic relationship to schizophrenia.
Assuntos
Doenças em Gêmeos/genética , Potenciais Evocados/genética , Esquizofrenia/genética , Estimulação Acústica , Adulto , Eletroencefalografia/estatística & dados numéricos , Potenciais Evocados P300/genética , Potenciais Evocados/fisiologia , Família , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Modelos Estatísticos , Inibição Neural/fisiologia , Linhagem , Fenótipo , Tempo de Reação/fisiologia , Esquizofrenia/fisiopatologia , Meio Social , Gêmeos Monozigóticos/genéticaRESUMO
Differences revealed by factor scores extracted by principal component analysis (PCA) from event-related potential (ERP) data of newborns with and without familial risk for dyslexia were examined and compared to results obtained by using original averaged ERPs. ERPs to consonant-vowel syllables (synthetic /ba/, /da/, /ga/; and natural /paa/, /taa/, /kaa/) were recorded from 26 at-risk and 23 control 1-7 day-old infants. The stimuli were presented equiprobably and with interstimulus intervals varying at random from 3,910 to 7,285 ms. Statistically significant between-group differences were found to be relatively similar irrespective of the methods of analysis (original ERPs vs. factor scores from PCA). Responses to /ga/ differed from those to /ba/ and /da/ between the groups in the right hemisphere at the latencies of 50-170 ms (Factor 4) and 540-630 ms (Factor 3). The groups differed also in their responses to /da/ in the posterior electrode sites at 740-940 ms (Factor 2). There were no group differences in the natural stimulus set. These results demonstrate that brain activation differences may be implicated in risk for dyslexia immediately after birth. The results also show that the PCA-ANOVA procedure is an effective way of identifying the group-related variance in the ERP-data when the component structure, such as those of infants, is not well-known in advance.
Assuntos
Dislexia/diagnóstico , Dislexia/genética , Eletroencefalografia/métodos , Potenciais Evocados/genética , Predisposição Genética para Doença/genética , Análise de Componente Principal/métodos , Estimulação Acústica , Análise de Variância , Encéfalo/fisiopatologia , Dislexia/fisiopatologia , Potenciais Evocados Auditivos/genética , Saúde da Família , Feminino , Lateralidade Funcional/genética , Variação Genética/genética , Humanos , Recém-Nascido , Testes de Linguagem , Masculino , Valor Preditivo dos Testes , Tempo de Reação/genética , Reprodutibilidade dos Testes , Comportamento Verbal/fisiologiaAssuntos
Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/fisiopatologia , Alcoolismo/genética , Alcoolismo/fisiopatologia , Potenciais Evocados/genética , Potenciais Evocados/fisiologia , Estimulação Acústica , Eletroencefalografia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Estimulação Luminosa , Caracteres SexuaisRESUMO
The P3(00) event-related brain potential (ERP) was elicited using auditory and visual stimuli in an oddball paradigm in 10 families, each consisting of a biologically related father, mother, and 2 children. P3 amplitude and latency measures from both stimulus modalities were more highly correlated between family members than between non-family individuals. Similar effects were found for the N1, P2 and N2 components. The results support findings from twin studies suggesting that genetic factors contribute to P3 morphological characteristics.