RESUMEN
The brain-specific tyrosine phosphatase, STEP (STriatal-Enriched protein tyrosine Phosphatase) is an important regulator of synaptic function. STEP normally opposes synaptic strengthening by increasing N-methyl D-aspartate glutamate receptor (NMDAR) internalization through dephosphorylation of GluN2B and inactivation of the kinases extracellular signal-regulated kinase 1/2 and Fyn. Here we show that STEP61 is elevated in the cortex in the Nrg1+/- knockout mouse model of schizophrenia (SZ). Genetic reduction or pharmacological inhibition of STEP prevents the loss of NMDARs from synaptic membranes and reverses behavioral deficits in Nrg1+/- mice. STEP61 protein is also increased in cortical lysates from the central nervous system-specific ErbB2/4 mouse model of SZ, as well as in human induced pluripotent stem cell (hiPSC)-derived forebrain neurons and Ngn2-induced excitatory neurons, from two independent SZ patient cohorts. In these selected SZ models, increased STEP61 protein levels likely reflect reduced ubiquitination and degradation. These convergent findings from mouse and hiPSC SZ models provide evidence for STEP61 dysfunction in SZ.
Asunto(s)
Proteínas Tirosina Fosfatasas/fisiología , Esquizofrenia/metabolismo , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neurregulina-1/genética , Neuronas/metabolismo , Fosforilación , Proteínas Tirosina Fosfatasas/genética , Ratas , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/genética , UbiquitinaciónRESUMEN
STriatal-Enriched protein tyrosine Phosphatase (STEP; PTPN5) is expressed in brain regions displaying adult neuroplasticity. STEP modulates neurotransmission by dephosphorylating regulatory tyrosine residues on its substrates. In this way, STEP inactivates extracellular-signal-regulated kinase 1/2 (ERK1/2), limiting the duration and spatial distribution of ERK signaling. Two additional substrates, the tyrosine kinase Fyn and the NR2B subunit of the N-methyl-d-aspartic acid receptor, link STEP to glutamate receptor internalization in the synapse. Thus, STEP may act through parallel pathways to oppose the development of experience-dependent synaptic plasticity. We examined the hypothesis that the absence of STEP facilitates amygdala-dependent behavioral and synaptic plasticity (i.e., fear conditioning and long-term potentiation) using STEP-deficient mice (STEP KO). These mice show no detectable expression of STEP in the brain along with increases in Tyr phosphorylation of STEP substrates. Here we demonstrate that STEP KO mice also display augmented fear conditioning as measured by an enhancement in conditioned suppression of instrumental response when a fear-associated conditioned stimulus was presented. Deletion of STEP also increases long-term potentiation and ERK phosphorylation in the lateral amygdala. The current experiments demonstrate that deletion of STEP can enhance experience-induced neuroplasticity and memory formation and identifies STEP as a target for pharmacological treatment aimed at improving the formation of long-term memories.
Asunto(s)
Amígdala del Cerebelo/metabolismo , Condicionamiento Operante/fisiología , Memoria/fisiología , Plasticidad Neuronal/fisiología , Proteínas Tirosina Fosfatasas no Receptoras/metabolismo , Amígdala del Cerebelo/citología , Análisis de Varianza , Animales , Biofisica , Estimulación Eléctrica , Potenciales Postsinápticos Excitadores/genética , Miedo/fisiología , Sistema de Señalización de MAP Quinasas/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Plasticidad Neuronal/genética , Técnicas de Placa-Clamp , Proteínas Tirosina Fosfatasas no Receptoras/genética , Esquema de Refuerzo , Refuerzo en PsicologíaRESUMEN
Glutamatergic signaling through N-methyl-D-aspartate receptors (NMDARs) is required for synaptic plasticity. Disruptions in glutamatergic signaling are proposed to contribute to the behavioral and cognitive deficits observed in schizophrenia (SZ). One possible source of compromised glutamatergic function in SZ is decreased surface expression of GluN2B-containing NMDARs. STEP(61) is a brain-enriched protein tyrosine phosphatase that dephosphorylates a regulatory tyrosine on GluN2B, thereby promoting its internalization. Here, we report that STEP(61) levels are significantly higher in the postmortem anterior cingulate cortex and dorsolateral prefrontal cortex of SZ patients, as well as in mice treated with the psychotomimetics MK-801 and phencyclidine (PCP). Accumulation of STEP(61) after MK-801 treatment is due to a disruption in the ubiquitin proteasome system that normally degrades STEP(61). STEP knockout mice are less sensitive to both the locomotor and cognitive effects of acute and chronic administration of PCP, supporting the functional relevance of increased STEP(61) levels in SZ. In addition, chronic treatment of mice with both typical and atypical antipsychotic medications results in a protein kinase A-mediated phosphorylation and inactivation of STEP(61) and, consequently, increased surface expression of GluN1/GluN2B receptors. Taken together, our findings suggest that STEP(61) accumulation may contribute to the pathophysiology of SZ. Moreover, we show a mechanistic link between neuroleptic treatment, STEP(61) inactivation and increased surface expression of NMDARs, consistent with the glutamate hypothesis of SZ.
Asunto(s)
Antipsicóticos/farmacología , Giro del Cíngulo/metabolismo , Fosforilación/efectos de los fármacos , Corteza Prefrontal/metabolismo , Proteínas Tirosina Fosfatasas no Receptoras/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Esquizofrenia/metabolismo , Análisis de Varianza , Animales , Antipsicóticos/uso terapéutico , Maleato de Dizocilpina/farmacología , Giro del Cíngulo/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fenciclidina/farmacología , Corteza Prefrontal/efectos de los fármacos , Proteínas Tirosina Fosfatasas no Receptoras/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/etiologíaRESUMEN
Fragile X syndrome (FXS), the most common inherited form of intellectual disability and prevailing known genetic basis of autism, is caused by an expansion in the Fmr1 gene that prevents transcription and translation of fragile X mental retardation protein (FMRP). FMRP binds to and controls translation of mRNAs downstream of metabotropic glutamate receptor (mGluR) activation. Recent work shows that FMRP interacts with the transcript encoding striatal-enriched protein tyrosine phosphatase (STEP; Ptpn5). STEP opposes synaptic strengthening and promotes synaptic weakening by dephosphorylating its substrates, including ERK1/2, p38, Fyn and Pyk2, and subunits of N-methyl-d-aspartate (NMDA) and AMPA receptors. Here, we show that basal levels of STEP are elevated and mGluR-dependent STEP synthesis is absent in Fmr1(KO) mice. We hypothesized that the weakened synaptic strength and behavioral abnormalities reported in FXS may be linked to excess levels of STEP. To test this hypothesis, we reduced or eliminated STEP genetically in Fmr1(KO) mice and assessed mice in a battery of behavioral tests. In addition to attenuating audiogenic seizures and seizure-induced c-Fos activation in the periaqueductal gray, genetically reducing STEP in Fmr1(KO) mice reversed characteristic social abnormalities, including approach, investigation and anxiety. Loss of STEP also corrected select nonsocial anxiety-related behaviors in Fmr1(KO) mice, such as light-side exploration in the light/dark box. Our findings indicate that genetically reducing STEP significantly diminishes seizures and restores select social and nonsocial anxiety-related behaviors in Fmr1(KO) mice, suggesting that strategies to inhibit STEP activity may be effective for treating patients with FXS.
Asunto(s)
Conducta Animal/fisiología , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Proteínas Tirosina Fosfatasas no Receptoras/genética , Animales , Conducta de Elección/fisiología , Modelos Animales de Enfermedad , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Hipocampo/metabolismo , Ratones , Ratones Noqueados , Actividad Motora/fisiología , Neuronas/metabolismo , Proteínas Tirosina Fosfatasas no Receptoras/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Receptores de Glutamato Metabotrópico/genética , Receptores de Glutamato Metabotrópico/metabolismo , Predominio Social , Sinaptosomas/metabolismoRESUMEN
Protein tyrosine phosphatases (PTPs) have emerged as a new class of signaling molecules that play important roles in the development and function of the central nervous system. They include both tyrosine-specific and dual-specific phosphatases. Based on their cellular localization they are also classified as receptor-like or intracellular PTP. However, the intracellular mechanisms by which these PTPs regulate cellular signaling pathways are not well understood. Evidence gathered to date provides some insight into the physiological function of these PTPs in the nervous system. In this review, we outline what is currently known about the functional role of PTPs expressed in the brain.
Asunto(s)
Encéfalo/enzimología , Proteínas Tirosina Fosfatasas/fisiología , Receptores de Superficie Celular/fisiología , Transducción de Señal/fisiología , Animales , Humanos , Péptidos y Proteínas de Señalización Intracelular , Proteínas Quinasas Activadas por Mitógenos/fisiología , Proteínas del Tejido Nervioso/fisiología , Proteína Tirosina Fosfatasa no Receptora Tipo 11 , Proteína Tirosina Fosfatasa no Receptora Tipo 6 , Proteínas Tirosina Fosfatasas no Receptoras , Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores , Proteínas Tirosina Fosfatasas Clase 5 Similares a ReceptoresRESUMEN
BACKGROUND: Some cases of Tourette's syndrome (TS) are hypothesized to be caused by autoantibodies that develop in response to a preceding group A beta hemolytic streptococcal infection. METHODS: To test this hypothesis, we looked for the presence ot total and IgG antibodies against neural, nuclear, cytoskeletal and streptococcal epitopes using indirect immunofluorescent assays and Western blot techniques in three patient groups: TS (n = 81), SC (n = 27), and a group of autoimmune disorders (n = 52) and in normal controls (n = 67). Subjects were ranked after titrations of autoantibodies from 0 to 227 according to their level of immunoreactivity. RESULTS: TS patients had a significantly higher mean rank for total antineural and antinuclear antibodies, as well as antistreptolysin O titers. However, among children and adolescents, only the total antinuclear antibodies were increased in TS patients compared to age matched controls. Compared to SC patients, TS patients had a significantly lower mean rank for total and IgG class antineural antibodies, significantly lower IgG class anticytoskeletal antibodies, and a significantly higher rank for total antinuclear antibodies. Compared to a mixed group of autoimmune disorders, the TS patients had a significantly lower mean rank for total and IgG class antineural antibodies, total and IgG class antinuclear antibodies, IgG class anticytoskeletal antibodies, and a significantly higher rank for antistreptococcal antibodies. CONCLUSIONS: TS patients had significantly higher levels of total antineural and antinuclear antibodies than did controls. Their relation to IgG class antineural and antinuclear antibodies, markers for prior streptococcal infection, and other clinical characteristics, especially chronological age, was equivocal.
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Anticuerpos Antinucleares/sangre , Anticuerpos Antibacterianos/sangre , Autoanticuerpos/sangre , Enfermedades Autoinmunes/inmunología , Corea/inmunología , Síndrome de Tourette/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Antiestreptolisina/sangre , Enfermedades Autoinmunes/diagnóstico , Niño , Corea/diagnóstico , Cuerpo Estriado/inmunología , Citoesqueleto/inmunología , Desoxirribonucleasas/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ratas , Síndrome de Tourette/diagnósticoAsunto(s)
Infecciones Estreptocócicas/epidemiología , Streptococcus pyogenes , Síndrome de Tourette/epidemiología , Síndrome de Tourette/microbiología , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Trastorno por Déficit de Atención con Hiperactividad/inmunología , Trastorno por Déficit de Atención con Hiperactividad/microbiología , Humanos , Trastorno Obsesivo Compulsivo/epidemiología , Trastorno Obsesivo Compulsivo/inmunología , Trastorno Obsesivo Compulsivo/microbiología , Infecciones Estreptocócicas/inmunología , Síndrome de Tourette/inmunologíaAsunto(s)
Encefalitis/genética , Miastenia Gravis/genética , Receptores de Glutamato/fisiología , Autoanticuerpos , Niño , Inhibidores de la Colinesterasa/farmacología , Encefalitis/complicaciones , Encefalitis/psicología , Regulación de la Expresión Génica , Humanos , Miastenia Gravis/complicaciones , Miastenia Gravis/psicología , Receptores de Glutamato/genética , Receptores de Glutamato/inmunologíaRESUMEN
The effects of heat on tic symptoms were studied in a sample of 78 adults with Tourette syndrome. 62 men and 16 women completed a survey concerning the type, onset, and course of their tics. 10 adult male subjects also participated in a thermal challenge during which ambient temperature was raised from 22 degrees C to 35 degrees C following a control period. Of the 78, 24% or 19 reported increased tics upon exposure to heat. Compared to the remaining 59 subjects, there were no differences in sex distribution, current age, or overall course of illness. In the thermal challenge, there was general increase in tics that was correlated with sweat rate (r = .55, p = .001). This effect was prominent in 5 of 10 subjects (rs = .29 to .63). There were no mean differences in current age, age of onset, or current severity of symptoms between the five subjects of each group. Tic symptoms in a subgroup of patients with Tourette syndrome may be sensitive to heat. Abnormal heat regulation is not a likely explanation for the observed increase in tics. The increase may be due to normal heat-loss mechanisms through dopaminergic pathways.
Asunto(s)
Regulación de la Temperatura Corporal/fisiología , Síndrome de Tourette/fisiopatología , Adulto , Femenino , Humanos , Masculino , Prevalencia , Índice de Severidad de la Enfermedad , Tics/epidemiología , Factores de Tiempo , Síndrome de Tourette/diagnósticoRESUMEN
The construction of the nervous system is regulated by genetic and environmental factors. In this article, we have highlighted some of the important molecules and genes that contribute to early stages of CNS development. Future research in the neurosciences will address how genetic and environmental factors interact with each other during brain development and in the mature nervous system.
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Daño Encefálico Crónico/genética , Encéfalo/anomalías , Adolescente , Encéfalo/patología , Daño Encefálico Crónico/diagnóstico , Diferenciación Celular/genética , Movimiento Celular/genética , Niño , Aberraciones Cromosómicas/genética , Trastornos de los Cromosomas , Predisposición Genética a la Enfermedad/genética , Humanos , Neuronas/patología , Medio SocialAsunto(s)
Anomalías Múltiples/genética , Sistema Nervioso Central/crecimiento & desarrollo , Trastornos de la Conducta Infantil/etiología , Cromosomas Humanos Par 22/genética , Eliminación de Gen , Anomalías Múltiples/epidemiología , Anomalías Múltiples/psicología , Sistema Nervioso Central/patología , Niño , Trastornos de la Conducta Infantil/epidemiología , Trastornos de la Conducta Infantil/genética , Regulación de la Expresión Génica , Humanos , PrevalenciaRESUMEN
OBJECTIVE: This study examined the frequency and age at onset of psychiatric disorders among children with rheumatic fever, Sydenham's chorea, or both and a comparison group. METHOD: Twenty children with rheumatic fever, 22 with Sydenham's chorea, and 20 comparison children were assessed by means of a semistructured interview and rating scales for tic disorders and obsessive-compulsive disorder. RESULTS: Obsessive-compulsive symptoms were more frequent in both the Sydenham's chorea and rheumatic fever groups than in the comparison group. The Sydenham's chorea group had a higher frequency of major depressive disorder, tic disorders, and attention deficit hyperactivity disorder (ADHD) than both the comparison and rheumatic fever groups. ADHD symptoms were associated with a higher risk of developing Sydenham's chorea. CONCLUSIONS: Both the rheumatic fever and Sydenham's chorea groups were associated with a higher risk of developing neuropsychiatric disorders than the comparison group. ADHD appears to be a risk factor for Sydenham's chorea in children with rheumatic fever.
Asunto(s)
Corea/diagnóstico , Trastornos Mentales/diagnóstico , Fiebre Reumática/diagnóstico , Factores de Edad , Edad de Inicio , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Brasil/epidemiología , Niño , Corea/epidemiología , Comorbilidad , Trastorno Depresivo/diagnóstico , Trastorno Depresivo/epidemiología , Femenino , Humanos , Masculino , Trastornos Mentales/epidemiología , Trastornos Mentales/psicología , Trastorno Obsesivo Compulsivo/diagnóstico , Trastorno Obsesivo Compulsivo/epidemiología , Prevalencia , Escalas de Valoración Psiquiátrica/estadística & datos numéricos , Fiebre Reumática/epidemiología , Fiebre Reumática/psicología , Tics/diagnóstico , Tics/epidemiologíaRESUMEN
OBJECTIVE: To review the literature over the past decade on the genetics of childhood neuropsychiatric disorders. METHOD: A computerized search was performed for articles published in the past decade, and selected papers were highlighted. RESULTS: The past decade of research has illuminated the complex genetics of early-onset mental disorders. Advances in statistical methodologies and laboratory-based gene-hunting techniques are laying the foundation for a deeper understanding of both the biological and environmental factors that contribute to mental illness. Researchers are on the verge of identifying and characterizing genetic vulnerabilities involved in common childhood psychiatric syndromes. CONCLUSIONS: Although the study of the genetics of childhood psychiatric disorders has advanced significantly over the past decade, considerable work remains. The identification of genes conferring vulnerability to psychiatric illnesses will have the potential to transform the field by providing insight into both biological and environmental determinants that contribute to serious developmental and psychiatric disorders in children and adolescents. These advances promise new understanding and new avenues for prevention and treatment. They will also present physicians and families with significant clinical and ethical challenges.
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Mapeo Cromosómico/métodos , Predisposición Genética a la Enfermedad/genética , Trastornos Mentales/genética , Mutación , Niño , Regulación de la Expresión Génica , Genotipo , Humanos , Fenotipo , SíndromeAsunto(s)
Síndrome de Angelman/genética , Cromosomas Humanos Par 15/genética , Ligasas/genética , Mutación , Femenino , Eliminación de Gen , Regulación de la Expresión Génica , Humanos , Masculino , Mutación Puntual , Síndrome de Prader-Willi/genética , Transcripción Genética , Ubiquitina-Proteína LigasasRESUMEN
The striatal-enriched protein tyrosine phosphatase (STEP) family is expressed within dopaminoceptive neurons of the CNS and is particularly enriched within the basal ganglia and related structures. Alternative splicing produces several isoforms that are found in a number of subcellular compartments, including postsynaptic densities of medium spiny neurons. The variants include STEP(61), a membrane-associated protein, and STEP(46), a cytosolic protein. The C terminals of these two isoforms are identical, whereas the N-terminal domain of STEP(61) contains a novel 172 amino acid sequence that includes several structural motifs not present in STEP(46). Amino acid sequencing revealed a number of potential phosphorylation sites in both STEP isoforms. Therefore, we investigated the role of phosphorylation in regulating STEP activity. Both STEP(61) and STEP(46) are phosphorylated on seryl residues by a cAMP-dependent protein kinase (PKA)-mediated pathway in striatal homogenates. The specific residues phosphorylated in STEP(61) were identified by site-directed mutagenesis and tryptic phosphopeptide mapping as Ser160 and Ser221, whereas the major site of phosphorylation in STEP(46) was shown to be Ser49. Ser160 is located within the unique N terminal of STEP(61). Ser221 and Ser49 are equivalent residues present in STEP(61) and STEP(46), respectively, and are located at the center of the kinase-interacting motif that has been implicated in protein-protein interactions. Phosphorylation at this site decreases the activity of STEP in vitro by reducing its affinity for its substrate. In vivo studies using striatal slices demonstrated that the neurotransmitter dopamine leads to the phosphorylation of STEP via activation of D1 receptors and PKA.
Asunto(s)
Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Receptores de Dopamina D1/metabolismo , Adenosina Trifosfato/metabolismo , Adenosina Trifosfato/farmacología , Animales , Dominio Catalítico , Cuerpo Estriado/química , Cuerpo Estriado/citología , Cuerpo Estriado/enzimología , Activación Enzimática/fisiología , Técnicas In Vitro , Masculino , Datos de Secuencia Molecular , Neuronas/química , Neuronas/enzimología , Fosfoproteínas/análisis , Radioisótopos de Fósforo , Fosforilación , Proteínas Tirosina Fosfatasas/antagonistas & inhibidores , Proteínas Tirosina Fosfatasas/química , Proteínas Tirosina Fosfatasas/metabolismo , Proteínas Tirosina Fosfatasas no Receptoras , Ratas , Ratas Sprague-Dawley , Transducción de Señal/fisiologíaRESUMEN
Protein tyrosine phosphatases play a critical role in controlling tyrosine phosphorylation levels of proteins. Ischemia induces changes in tyrosine phosphorylation. As part of our investigations of the mechanisms responsible for these changes, we studied the effects of cerebral hypoxia-ischemia in 7-day-old (P7) and P21 rat brains on expression of the STEP (striatal enriched phosphatase) family of protein tyrosine phosphatases. P7 and P21 rats were subjected to unilateral hypoxia-ischemia, and brains were analyzed at various intervals of recovery for the presence of STEP. Hypoxia-ischemia induced the formation of a low Mr isoform of STEP, STEP33, in the ipsilateral (damaged) hemisphere but not in the contralateral (undamaged) side. STEP33 produced as a result of ischemia was located exclusively in the cell soluble fraction. In P21 rats, the ischemia-induced elevation in STEP33 was delayed relative to P7 rats. STEP33 was produced by digestion of postsynaptic densities with calpain I and by exposure of NT2/D1 cells expressing STEP to the calcium ionophore A23187. The results suggest that ischemia-induced calcium influx results in the calcium-dependent proteolysis of membrane-associated STEP61 and the concomitant release of STEP33 into the cytoplasm.
Asunto(s)
Hipoxia-Isquemia Encefálica/metabolismo , Isoenzimas/biosíntesis , Envejecimiento , Animales , Femenino , Peso Molecular , Proteínas Tirosina Fosfatasas/biosíntesis , Proteínas Tirosina Fosfatasas no Receptoras , Ratas , Ratas WistarRESUMEN
Striatal enriched phosphatase (STEP) is a family of protein tyrosine phosphatases enriched within the CNS. A member of this family, STEP61, is a membrane-associated protein located in postsynaptic densities of striatal neurons. In this study, we demonstrate that STEP61, is cleaved into smaller isoforms. To clarify the mechanism of cleavage, STEP61 was transiently expressed in NT2/D1 neuronal precursor cells. Exposure of transfected cells to the calcium ionophore, A23187, or to thapsigargin resulted in the rapid cleavage of STEP61. Pretreatment with the calpain inhibitor, calpeptin, or EGTA prevented proteolysis. One of the cleavage products has a relative molecular mass of 33 kDa (STEP33). A protein with the identical mobility is detected following calpain treatment of STEP61 fusion protein or postsynaptic densities purified from rat striatum. Exposure of primary neuronal cultures to glutamate also led to a significant increase in the concentration of a low molecular weight form of STEP. Taken together, these results suggest that in response to a rapid influx of calcium, STEP61, is proteolytically cleaved by calpain, leading to the release of a smaller isoform. This model may explain the rapid appearance of STEP33 in response to transient hypoxia-ischemia in the brain as cells attempt to counter the increase in tyrosine phosphorylation levels following neuronal insults.