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1.
Brain Behav Immun ; 121: 74-86, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39043346

RESUMEN

Protein Kinase RNA-activated (PKR) is an enzyme that plays a role in many systemic processes, including modulation of inflammation, and is implicated in neurodegenerative diseases, such as Alzheimer's disease (AD). PKR phosphorylation results in the production of several cytokines involved in the regulation / modulation of sleep, including interleukin-1ß, tumor necrosis factor-α and interferon-γ. We hypothesized targeting PKR would alter spontaneous sleep of mice, attenuate responses to sleep deprivation, and inhibit responses to immune challenge. To test these hypotheses, we determined the sleep-wake phenotype of mice lacking PKR (knockout; PKR-/-) during undisturbed baseline conditions; in responses to six hours of sleep deprivation; and after immune challenge with lipopolysaccharide (LPS). Adult male mice (C57BL/6J, n = 7; PKR-/-, n = 7) were surgically instrumented with EEG recording electrodes and an intraperitoneal microchip to record core body temperature. During undisturbed baseline conditions, PKR -/- mice spent more time in non-rapid eye movement sleep (NREMS) and rapid-eye movement sleep (REMS), and less time awake at the beginning of the dark period of the light:dark cycle. Delta power during NREMS, a measure of sleep depth, was less in PKR-/- mice during the dark period, and core body temperatures were lower during the light period. Both mouse strains responded to sleep deprivation with increased NREMS and REMS, although these changes did not differ substantively between strains. The initial increase in delta power during NREMS after sleep deprivation was greater in PKR-/- mice, suggesting a faster buildup of sleep pressure with prolonged waking. Immune challenge with LPS increased NREMS and inhibited REMS to the same extent in both mouse strains, whereas the initial LPS-induced suppression of delta power during NREMS was greater in PKR-/- mice. Because sleep regulatory and immune responsive systems in brain are redundant and overlapping, other mediators and signaling pathways in addition to PKR are involved in the responses to acute sleep deprivation and LPS immune challenge.


Asunto(s)
Ratones Endogámicos C57BL , Ratones Noqueados , Privación de Sueño , Sueño , Vigilia , eIF-2 Quinasa , Animales , Privación de Sueño/inmunología , Privación de Sueño/metabolismo , Masculino , Ratones , Vigilia/fisiología , eIF-2 Quinasa/metabolismo , Sueño/fisiología , Lipopolisacáridos/farmacología , Electroencefalografía , Temperatura Corporal/fisiología , Sueño REM/fisiología
2.
Nature ; 511(7508): 236-40, 2014 Jul 10.
Artículo en Inglés | MEDLINE | ID: mdl-24870235

RESUMEN

Although considerable evidence suggests that the chemical synapse is a lynchpin underlying affective disorders, how molecular insults differentially affect specific synaptic connections remains poorly understood. For instance, Neurexin 1a and 2 (NRXN1 and NRXN2) and CNTNAP2 (also known as CASPR2), all members of the neurexin superfamily of transmembrane molecules, have been implicated in neuropsychiatric disorders. However, their loss leads to deficits that have been best characterized with regard to their effect on excitatory cells. Notably, other disease-associated genes such as BDNF and ERBB4 implicate specific interneuron synapses in psychiatric disorders. Consistent with this, cortical interneuron dysfunction has been linked to epilepsy, schizophrenia and autism. Using a microarray screen that focused upon synapse-associated molecules, we identified Cntnap4 (contactin associated protein-like 4, also known as Caspr4) as highly enriched in developing murine interneurons. In this study we show that Cntnap4 is localized presynaptically and its loss leads to a reduction in the output of cortical parvalbumin (PV)-positive GABAergic (γ-aminobutyric acid producing) basket cells. Paradoxically, the loss of Cntnap4 augments midbrain dopaminergic release in the nucleus accumbens. In Cntnap4 mutant mice, synaptic defects in these disease-relevant neuronal populations are mirrored by sensory-motor gating and grooming endophenotypes; these symptoms could be pharmacologically reversed, providing promise for therapeutic intervention in psychiatric disorders.


Asunto(s)
Dopamina/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Transducción de Señal , Transmisión Sináptica/genética , Ácido gamma-Aminobutírico/metabolismo , Animales , Antipsicóticos/farmacología , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Sinapsis Eléctricas/genética , Sinapsis Eléctricas/ultraestructura , Femenino , Genotipo , Humanos , Masculino , Ratones , Polimorfismo de Nucleótido Simple
3.
Neuroscience ; 376: 117-126, 2018 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-29454635

RESUMEN

Down syndrome (DS) results from the triplication of genes located on human chromosome 21 (Hsa21). Though many cognitive and behavioral impairments are associated with DS, sleep disturbances remain poorly understood despite being a reported phenotype in approximately 60% of individuals diagnosed with DS. In this study, sleep and electroencephalography (EEG) oscillations were recorded from aged (12-14 mos.) Dp(16)1Yey/+ mice (Dp16), a mouse model of DS. We observed disrupted sleep demonstrated by increased activity during the dark phase and increased time awake at the expense of NREM sleep compared to wild-type mice. In addition, we found that Dp16 mice display significant differences in relative EEG power distribution among oscillation frequencies in both sleep and awake states. These results in Dp16 mice are consistent with sleep disturbances found in individuals with DS, and the abnormal EEG oscillations in aged Dp16 mice suggest a potential role for GABAergic activity in these sleep and EEG abnormalities. These sleep and EEG data reflect underlying differences in neuronal activity at the network level and thus are causative agents rather than merely symptoms of DS.


Asunto(s)
Encéfalo/fisiopatología , Síndrome de Down/fisiopatología , Sueño/fisiología , Animales , Ondas Encefálicas , Modelos Animales de Enfermedad , Electrocorticografía , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Actividad Motora , Vigilia
4.
J Neurosci ; 23(15): 6362-72, 2003 Jul 16.
Artículo en Inglés | MEDLINE | ID: mdl-12867522

RESUMEN

Analyses of early molecular and cellular events associated with long-term plasticity remain hampered in Drosophila by the lack of an acute procedure to activate signal transduction pathways, gene expression patterns, and other early cellular events associated with long-term synaptic change. Here we describe the development and first use of such a technique. Bursts of neural activity induced in Drosophila comatosets and CaP60A Kumts mutants, with conditional defects in N-ethylmaleimide-sensitive fusion factor 1 and sarco-endoplasmic reticulum Ca2+ ATPase, respectively, result in persistent (>4 hr) activation of neuronal extracellular signal-regulated kinase (ERK). ERK activation at the larval neuromuscular junction coincides with rapid reduction of synaptic Fasciclin II; in soma, nuclear translocation of activated ERK occurs together with increased transcription of the immediate-early genes Fos and c/EBP (CCAAT element binding protein). The effect of "seizure-stimulation" on ERK activation requires neural activity and is mediated through activation of MEK (MAPK/erk kinase), the MAPKK (mitogen-activated protein kinase kinase) that functions upstream of ERK. Our results (1) provide direct proof for the conservation of synaptic signaling pathways in arthropods, (2) demonstrate the utility of a new genetic tool for analysis of synaptic plasticity in Drosophila, and (3) potentially enable new proteomic and genomic analyses of activity-regulated molecules in an important model organism.


Asunto(s)
Núcleo Celular/diagnóstico por imagen , Drosophila melanogaster/fisiología , Transducción de Señal/fisiología , Sinapsis/fisiología , Proteínas de Transporte Vesicular , Transporte Activo de Núcleo Celular , Animales , Proteínas Potenciadoras de Unión a CCAAT/genética , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , ATPasas Transportadoras de Calcio/genética , Proteínas Portadoras/genética , Moléculas de Adhesión Celular Neuronal/metabolismo , Núcleo Celular/metabolismo , Sistema Nervioso Central/citología , Sistema Nervioso Central/fisiología , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Regulación de la Expresión Génica , Larva , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Mutación , Proteínas Sensibles a N-Etilmaleimida , Unión Neuromuscular/fisiología , Plasticidad Neuronal/fisiología , Neuronas/metabolismo , Neuronas/fisiología , Parálisis/fisiopatología , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico , Convulsiones/fisiopatología , Sinapsis/metabolismo , Temperatura , Ultrasonografía
5.
Genes Brain Behav ; 11(3): 332-41, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22268788

RESUMEN

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and autism. The protein (FMRP) encoded by the fragile X mental retardation gene (FMR1), is an RNA-binding protein linked to translational control. Recently, in the Fmr1 knockout mouse model of FXS, dysregulated translation initiation signaling was observed. To investigate whether an altered signaling was also a feature of subjects with FXS compared to typical developing controls, we isolated total RNA and translational control proteins from lymphocytes of subjects from both groups (38 FXS and 14 TD). Although we did not observe any difference in the expression level of messenger RNAs (mRNAs) for translational initiation control proteins isolated from participant with FXS, we found increased phosphorylation of the mammalian target of rapamycin (mTOR) substrate, p70 ribosomal subunit 6 kinase1 (S6K1) and of the mTOR regulator, the serine/threonine protein kinase (Akt), in their protein lysates. In addition, we observed increased phosphorylation of the cap binding protein eukaryotic initiation factor 4E (eIF4E) suggesting that protein synthesis is upregulated in FXS. Similar to the findings in lymphocytes, we observed increased phosphorylation of S6K1 in brain tissue from patients with FXS (n = 4) compared to normal age-matched controls (n = 4). Finally, we detected increased expression of the cytoplasmic FMR1-interacting protein 2 (CYFIP2), a known FMRP interactor. This data verify and extend previous findings using lymphocytes for studies of neuropsychiatric disorders and provide evidence that misregulation of mTOR signaling observed in the FXS mouse model also occurs in human FXS and may provide useful biomarkers for designing targeted treatments in FXS.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/biosíntesis , Síndrome del Cromosoma X Frágil/metabolismo , Transducción de Señal/fisiología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Regulación hacia Arriba/fisiología , Proteínas Adaptadoras Transductoras de Señales/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Síndrome del Cromosoma X Frágil/genética , Regulación de la Expresión Génica/fisiología , Humanos , Masculino , Persona de Mediana Edad , Cultivo Primario de Células , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/fisiología , Adulto Joven
6.
Arch Insect Biochem Physiol ; 43(1): 16-21, 2000 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-10613959

RESUMEN

The cDNA sequence for apolipophorin-III from two strains of Bombyx mori (N4 and P50) and the Japanese and Chinese strains of Bombyx mandarina were determined. Both the cDNA and deduced amino acid sequences of the four apolipophorin-IIIs were highly similar (95-98%). The four Bombyx sequences also showed significant similarity to the sequence of apolipophorin-III from another lepidopteran, Manduca sexta (83-84%), particularly in the five amphipathic alpha-helices that are proposed to play a critical role in the binding of apolipophorin-III to lipophorin. In the coding region, the nucleotide sequences for the Chinese strain of B. mandarina and the P50 strain of B. mori were identical, supporting the suggestion that P50 is the current strain most closely related to the original domesticated strain. The N4 strain of B. mori is more closely related to these two strains than is the Japanese strain of B. mandarina, suggesting that Japanese strain of B. mandarina separated from the Chinese strain of B. mandarina before domestication of B. mori. Arch.


Asunto(s)
Apolipoproteínas/química , Bombyx/genética , Secuencia de Aminoácidos , Animales , Bombyx/metabolismo , ADN Complementario/química , Datos de Secuencia Molecular
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