RESUMEN

The present manuscript stems from evidence, which indicates that specific wavelength produce an activation of the autophagy pathway in the retina. These effects were recently reported to synergize with the autophagy-inducing properties of specific phytochemicals. The combined administration of photo-modulation and phytochemicals was recently shown to have a strong potential in eliciting the recovery in the course of retinal degeneration and it was suggested as a non-invasive approach named "Lugano protocol" to treat age-related macular degeneration (AMD). Recent translational findings indicate that the protective role of autophagy may extend also to acute neuronal injuries including traumatic neuronal damage. At the same time, very recent investigations indicate that autophagy activation and retinal anatomical recovery may benefit from sound exposure. Therefore, in the present study, the anatomical rescue of a traumatic neuronal loss at macular level was investigated in a patient with idiopathic macular hole by using a combined approach of physical and chemical non-invasive treatments. In detail, light exposure was administered in combination with sound pulses to the affected retina. This treatment was supplemented by phytochemicals known to act as autophagy inducers, which were administered orally for 6 months. This combined administration of light and sound with nutraceuticals reported here as Advanced Lugano's Protocol (ALP) produced a remarkable effect in the anatomical architecture of the retina affected by the macular hole. The anatomical recovery was almost complete at roughly one year after diagnosis and beginning of treatment. The structural healing of the macular hole was concomitant with a strong improvement of visual acuity and the disappearance of metamorphopsia. The present findings are discussed in the light of a synergism shown at neuronal level between light and sound in the presence of phytochemicals to stimulate autophagy and promote proliferation and neuronal differentiation of retinal stem cells.

Asunto(s)

Perforaciones de la Retina , Suplementos Dietéticos , Humanos , Retina , Perforaciones de la Retina/cirugía , Agudeza Visual , Vitrectomía/métodos

RESUMEN

The occurrence of pure light exerts a variety of effects in the human body, which span from behavioral alterations, such as light-driven automatic motor activity, cognition and mood to more archaic vegetative functions, which encompass most organs of the body with remarkable effects on the cardiovascular system. Although empirical evidence clearly indicates occurrence of these widespread effects, the anatomical correlates and long-lasting changes within putatively specific neuronal circuitries remain largely unexplored. A specific role is supposed to take place for catecholamine containing neurons in the core of the brainstem reticular formation, which produces a widespread release of noradrenaline in the forebrain while controlling the vegetative nervous system. An indirect as well as a direct (mono-synaptic) retino-brainstem pathway is hypothesized to rise from a subtype of intrinsically photosensitive retinal ganglion cells (iPRGCs), subtype M1, which do stain for Brn3b, and project to the pre-tectal region (including the olivary pre-tectal nucleus). This pathway provides profuse axon collaterals, which spread to the periacqueductal gray and dorsal raphe nuclei. According to this evidence, a retino-reticular monosynaptic system occurs, which powerfully modulate the noradrenergic hub of reticular nuclei in the lateral column of the brainstem reticular formation. These nuclei, which are evidenced in the present study, provide the anatomical basis to induce behavioral and cardiovascular modulation. The occurrence of a highly interconnected network within these nuclei is responsible for light driven plastic effects, which may alter persistently behavior and vegetative functions as the consequence of long-lasting alterations in the environmental light stimulation of the retina. These changes, which occur within the core of an archaic circuitry such as the noradrenaline-containing neurons of the reticular formation, recapitulate, within the CNS, ancestral effects of light-driven changes, which can be detected already within the retina itself at the level of multipotent photic cells.

Asunto(s)

Sistema Cardiovascular , Formación Reticular , Tronco Encefálico , Humanos , Norepinefrina , Formación Reticular/fisiología , Células Ganglionares de la Retina/fisiología

RESUMEN

Locus Coeruleus (LC) is the main noradrenergic nucleus of the brain, which is involved in many physiological functions including cognition; its impairment may be crucial in the neurobiology of a variety of brain diseases. Locus Coeruleus-Magnetic Resonance Imaging (LC-MRI) allows to identify in vivo LC in humans. Thus, a variety of research teams have been using LC-MRI to estimate LC integrity in normal aging and in patients affected by neurodegenerative disorders, where LC integrity my work as a biomarker. A number of variations between LC-MRI studies exist, concerning post-acquisition analysis and whether this had been performed within MRI native space or in ad hoc-built MRI template space. Moreover, the reproducibility and reliability of this tool is still to be explored. Therefore, in the present study, we analyzed a group of neurologically healthy, cognitively intact elderly subjects, using both a native space- and a template space-based LC-MRI analysis. We found a good inter-method agreement, particularly considering the LC Contrast Ratio. The template space-based approach provided a higher spatial resolution, lower operator-dependency, and allowed the analysis of LC topography. Our ad hoc-developed LC template showed LC morphological data that were in line with templates published very recently. Remarkably, present data significantly overlapped with a recently published LC "metaMask", that had been obtained by averaging the results of a variety of previous LC-MRI studies. Thus, such a template space-based approach may pave the way to a standardized LC-MRI analysis and to be used in future clinic-anatomical correlations.

Asunto(s)

Locus Coeruleus , Imagen por Resonancia Magnética , Anciano , Envejecimiento , Humanos , Locus Coeruleus/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Espectroscopía de Resonancia Magnética , Reproducibilidad de los Resultados

RESUMEN

Increasing findings indicate that a dysfunction in the autophagy machinery is common during retinal degeneration. The present article provides evidence showing that an autophagy defect in the outer retinal layers is commonly described at the onset of retinal degeneration. These findings involve a number of structures placed at the border between the inner choroid and the outer retina encompassing the choriocapillaris, the Bruch's membrane, photoreceptors and Mueller cells. At the center of these anatomical substrates are placed cells forming the retinal pigment epithelium (RPE), where autophagy seems to play most of its effects. In fact, a failure of the autophagy flux is mostly severe at the level of RPE. Among various retinal degenerative disorders, age-related macular degeneration (AMD) is mostly affected by a damage to RPE, which can be reproduced by inhibiting the autophagy machinery and it can be counteracted by the activation of the autophagy pathway. In the present manuscript evidence is provided that such a severe impairment of retinal autophagy may be counteracted by administration of a number of phytochemicals, which possess a strong stimulatory activity on autophagy. Likewise, natural light stimulation administered in the form of pulsatile specific wavelengths is capable of inducing autophagy within the retina. This dual approach to stimulate autophagy is further strengthened by the interaction of light with phytochemicals which is shown to activate the chemical properties of these natural molecules in sustaining retinal integrity. The beneficial effects of photo-biomodulation combined with phytochemicals is based on the removal of toxic lipid, sugar and protein species along with the stimulation of mitochondrial turn-over. Additional effects of autophagy stimulation under the combined effects of nutraceuticals and light pulses are discussed concerning stimulation of retinal stem cells which partly correspond to a subpopulation of RPE cells.

Asunto(s)

Degeneración Retiniana , Humanos , Retina , Nutrientes , Epitelio Pigmentado de la Retina , Autofagia

RESUMEN

The present article presents a case report and discusses the neurobiology underlying the potential neuro-repair induced by combined administration of phytochemicals in a patient undergoing photo-bio-modulation (PBM), which improves anatomical and clinical abnormalities in the course of age-related macular degeneration (AMD). After combined treatments the patient with nutraceuticals and PBM had noticeable improvement of retinal tissue with excellent vision for her age and no worsening of corneal guttae, which was present at the time of diagnosis. The present treatment was tailored, based on translational evidence, to improve the autophagy pathway, which is a key determinant in the onset and progression of AMD. In fact, treatment with specific patterns of light exposure combined with specific phytochemicals, may synergize in improving the microanatomy of the retina by restoring its neurobiology. The combination of light exposure, at selective wavelengths, with the effects produced by the intake of specific phytochemicals to treat AMD is reported here as "Lugano Protocol". Such a clinical protocol represents an "in progress" development backed up by translational research. In fact, recent evidence indicates that, specific phytochemicals, when administered in combination may promote anatomical and functional integrity within the retina. These in turn synergize with analogous effects produced by specific wavelengths, when administered at specific time intervals. The synergism between specific light and combined phytochemicals is discussed at molecular level, where recent data indicate how these treatments, when delivered according to specific patterns, may enhance autophagy in the retina. The improvement of retinal morphology and visual acuity, observed in this case report is thoroughly discussed in the light of the key role of autophagy in regulating the integrity of the retinal epithelium. Despite exciting, and consistent with translational evidence, the clinical report of a disease modifying effect during AMD owns the inherent limit of a case report, which requires wide validation in large number of patients. The potential effectiveness of "Lugano protocol" may apply to other types of retinal degenerations, where common alterations in the autophagy pathway do occur. Thus, such a therapeutic approach may extend to a common late stage of retinal trans-synaptic degeneration, where maladaptive plasticity during several types of retinal degenerative disorders eventually converge.

Asunto(s)

Degeneración Macular , Degeneración Retiniana , Suplementos Dietéticos , Femenino , Humanos , Degeneración Macular/terapia , Retina , Degeneración Retiniana/terapia , Agudeza Visual

RESUMEN

BACKGROUND: The food-rich environment in which we live makes the regulation of food choices a very complex phenomenon determined by many factors, as well as their interactions. Much evidence suggests that the sensory perception of food can be considered as a central factor affecting individual food choices. Despite this, the approaches used to study the various food aspects usually do not distinguish between different types of food. METHODS: In the present study, a large and heterogeneous sample of 1149 participants aged 7-90 years was asked to judge food images that were labelled differently (i.e. Raw versus Cooked, Natural versus Transformed and Simple versus Complex) with respect to arousal, valence, typicality and familiarity. RESULTS: We observed that, across food dimensions (i.e., Raw versus Cooked, Natural versus Transformed and Simple versus Complex), arousal, valence and typicality judgments were principally affected by a subjective hunger level and gender (and their interaction) and, to a lesser extent, by age. CONCLUSIONS: As a whole, our findings suggest that the level of transformation (which includes cooking) and the complexity of a foodstuff could at least partially affect food processing, entailing that future research should also address these features.

Asunto(s)

Afecto , Nivel de Alerta , Dieta/psicología , Preferencias Alimentarias , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Niño , Ingestión de Energía , Femenino , Alimentos , Manipulación de Alimentos , Humanos , Hambre , Masculino , Persona de Mediana Edad , Percepción , Factores Sexuales , Adulto Joven

RESUMEN

Experiencing an adverse childhood and parental neglect is a risk factor for depression in the adult population. Patients with a history of traumatic childhood develop a subtype of depression that is characterized by earlier onset, poor treatment response and more severe symptoms. The long-lasting molecular mechanisms that are engaged during early traumatic events and determine the risk for depression are poorly understood. In this study, we altered adult depression-like behavior in mice by applying juvenile isolation stress. We found that this behavioral phenotype was associated with a reduction in the levels of the deacetylase sirtuin1 (SIRT1) in the brain and in peripheral blood mononuclear cells. Notably, peripheral blood mRNA expression of SIRT1 predicted the extent of behavioral despair only when depression-like behavior was induced by juvenile--but not adult--stress, implicating SIRT1 in the regulation of adult behavior at early ages. Consistent with this hypothesis, pharmacological modulation of SIRT1 during juvenile age altered the depression-like behavior in naive mice. We also performed a pilot study in humans, in which the blood levels of SIRT1 correlated significantly with the severity of symptoms in major depression patients, especially in those who received less parental care during childhood. On the basis of these novel findings, we propose the involvement of SIRT1 in the long-term consequences of adverse childhood experiences.

Asunto(s)

Conducta Animal , Encéfalo/metabolismo , Depresión/metabolismo , Sirtuina 1/metabolismo , Aislamiento Social/psicología , Estrés Psicológico/metabolismo , Animales , Depresión/psicología , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Factores de Riesgo , Estrés Psicológico/psicología

RESUMEN

Neuregulin 1 (NRG1) is a trophic factor that has an essential role in the nervous system by modulating neurodevelopment, neurotransmission and synaptic plasticity. Despite the evidence that NRG1 and its receptors, ErbB tyrosine kinases, are expressed in mesencephalic dopaminergic nuclei and their functional alterations are reported in schizophrenia and Parkinson's disease, the role of NRG1/ErbB signalling in dopaminergic neurons remains unclear. Here we found that NRG1 selectively increases the metabotropic glutamate receptor 1 (mGluR1)-activated currents by inducing synthesis and trafficking to membrane of functional receptors and stimulates phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin (PI3K-Akt-mTOR) pathway, which is required for mGluR1 function. Notably, an endogenous NRG1/ErbB tone is necessary to maintain mGluR1 function, by preserving its surface membrane expression in dopaminergic neurons. Consequently, it enables striatal mGluR1-induced dopamine outflow in in vivo conditions. Our results identify a novel role of NRG1 in the dopaminergic neurons, whose functional alteration might contribute to devastating diseases, such as schizophrenia and Parkinson's disease.

Asunto(s)

Neuronas Dopaminérgicas/fisiología , Mesencéfalo/fisiología , Neurregulina-1/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Animales , Dopamina/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Receptores ErbB/metabolismo , Masculino , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Mesencéfalo/efectos de los fármacos , Microdiálisis , Técnicas de Placa-Clamp , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Técnicas de Cultivo de Tejidos

RESUMEN

The effect of a high (chocolate) versus low fat/sugar (chow) food on a conditioned-place-preference (CPP) task was evaluated in marmoset monkeys. Anxiety-related behaviors and cortisol levels before and after the CPP task were also measured. Subjects were habituated to a two-compartment CPP box and then, on alternate days, had access to only one compartment during daily 15-min conditionings, for a total of 14 trials. Marmosets were provisioned with chocolate chips in the CC-paired compartment on odd-numbered trials and standard chow in the CW-paired compartment on even-numbered trials. They were then tested for preferring the CC-paired context after a 24-h interval. During the conditioning, a significantly greater amount (in kcal/trial) of chocolate was consumed than chow, yet the foraging pattern of both food types was similar. On the test trial, the time spent in the CC-paired context increased significantly compared to pre-CPP levels, yet this response was not readily predicted by baseline behavioral or cortisol levels. Also, the chocolate CPP response was positively correlated with foraging time, rather than the amount of calories consumed. The sudden absence of the food increased exploration, while the chocolate CPP effect was associated with vigilance - both anxiety-related behaviors in marmosets. This behavioral profile occurred regardless of any concomitant change or correlation with cortisol. Therefore, the high fat/sugar food was more prone to be overly consumed by the marmosets, to induce a CPP response and to lead to anxiety-related behavior in its absence.

Asunto(s)

Alimentación Animal , Conducta Apetitiva/fisiología , Cacao , Condicionamiento Psicológico/fisiología , Hidrocortisona/sangre , Percepción Espacial/fisiología , Animales , Ansiedad/fisiopatología , Callithrix , Ingestión de Energía , Conducta Exploratoria/fisiología , Femenino , Masculino

RESUMEN

Highly palatible foods may induce addiction-related behaviors. However, this has yet to be established in non-human primates. Therefore, we evaluated whether marmoset monkeys (Calllithrix penicillata) acquire a conditioned-place-preference (CPP) for chocolate and if this response is detectable after a 24-h and 15-day period. Subjects were first habituated to a two-compartment CPP box and then randomly assigned to a chocolate or control group. Thereafter, they were given access to only one compartment during daily 15-min conditionings, held on six consecutive days. On each trial, the chocolate group received pieces of chocolate (50g) in this context, whereas controls were not given a food reward. Marmosets were subsequently tested for preferring this (food) paired context after a 24-h and 15-day interval. During conditioning, individual foraging and the amount of chocolate ingested by each pair of the chocolate group remained constant. However, compared to pre-CPP levels, the time spent inside/in contact with the conditioned compartment increased significantly, while the latency to first entry decreased on both post-CPP intervals. For controls, the parameters remained unaltered. Thus, chocolate induced a persistent CPP response-an aspect usually associated with drug-related rewards.

Asunto(s)

Cacao , Callithrix/fisiología , Condicionamiento Psicológico/fisiología , Conducta Alimentaria/fisiología , Memoria a Largo Plazo/fisiología , Recompensa , Animales , Femenino , Masculino , Distribución Aleatoria

RESUMEN

Although the wake-promoting drug modafinil has been shown to bind quite exclusively to the dopamine transporter (DAT), its action in the brain has been thought to be partially independent from the facilitation of the dopaminergic signals. Here we used electrophysiological and amperometric techniques to investigate the effects of modafinil on the dopaminergic neurons of the substantia nigra pars compacta (SNpc) and on the synaptic overflow of dopamine in the dorsal striatum from the sliced tissue of wild-type and cocaine-insensitive genetically modified mice (DAT-CI). Moreover, we examined the consequences of modafinil administration on the locomotor behavior of wild-type and DAT-CI mice. In in vitro experiments, modafinil inhibited the spontaneous firing discharge of the dopaminergic neurons. More consistently, it potentiated firing inhibition and the membrane responses caused by exogenously applied dopamine on these cells. Furthermore, it augmented the stimulus-evoked outflow of DA in the striatum. Noteworthy, modafinil caused locomotor activation in wild-type mice. On the other hand, neither the electrophysiological nor the behavioral effects of modafinil were detected in DAT-CI animals. These results demonstrate that modafinil potentiates brain dopaminergic signals via DAT inhibition by acting at the same binding site of cocaine. Therefore, this mechanism of action explains most of the pharmacological properties of this compound in the clinical setting.

Asunto(s)

Compuestos de Bencidrilo/farmacología , Neuronas Dopaminérgicas/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Promotores de la Vigilia/farmacología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Cocaína/farmacología , Dopamina/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Ratones , Ratones Mutantes , Modafinilo , Técnicas de Placa-Clamp

RESUMEN

The impact of stress is widely recognized in the etiology of multiple disorders. In particular, psychological stress may increase the risk of cardiovascular, metabolic, immune, and mood disorders. Several genes are considered potential candidates to account for the deleterious consequences of stress and recent data point to role of Vgf. VGF mRNA is abundantly expressed in the hypothalamus, where it has been involved in metabolism and energy homeostasis; more recently a link between VGF-derived peptides and mood disorders has been highlighted. The following experiments were performed to address the contribution of the VGF-system to stress induced changes in mice: the distribution of VGF immuno-reactivity in hypothalamic nuclei and its modulation by social stress; the role of VGF-derived peptide TLQP-21 in plasma catecholamine release induced by acute restraint stress (RS); the efficacy of chronic TLQP-21 in a mouse model of chronic subordination stress (CSS). VGF fibers were found in high density in arcuate, dorsomedial, and suprachiasmatic and, at lower density, in lateral, paraventricular, and ventromedial hypothalamic nuclei. Central administration of either 2 or 4 mM TLQP-21 acutely altered the biphasic serum epinephrine release and decreased norepinephrine serum levels in response to RS. Finally, 28-day of 40 µg/day TLQP-21 treatment increased CSS-induced social avoidance of an unfamiliar conspecific. Overall these data support a role for TLQP-21 in stress responses providing a promising starting point to further elucidate its role as a player in stress-related human pathologies.

Asunto(s)

Hipotálamo/metabolismo , Neuropéptidos/metabolismo , Fragmentos de Péptidos/farmacología , Fragmentos de Péptidos/uso terapéutico , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/metabolismo , Animales , Reacción de Prevención/efectos de los fármacos , Catecolaminas/sangre , Modelos Animales de Enfermedad , Hipotálamo/efectos de los fármacos , Infusiones Subcutáneas , Inyecciones Intraventriculares , Masculino , Ratones , Ratones Endogámicos ICR , Actividad Motora/efectos de los fármacos , Factores de Crecimiento Nervioso , Fragmentos de Péptidos/administración & dosificación , Conducta Social , Estrés Psicológico/sangre

RESUMEN

Autism is a severe developmental disorder, whose pathogenetic underpinnings are still largely unknown. Temporocortical gray matter from six matched patient-control pairs was used to perform post-mortem biochemical and genetic studies of the mitochondrial aspartate/glutamate carrier (AGC), which participates in the aspartate/malate reduced nicotinamide adenine dinucleotide shuttle and is physiologically activated by calcium (Ca(2+)). AGC transport rates were significantly higher in tissue homogenates from all six patients, including those with no history of seizures and with normal electroencephalograms prior to death. This increase was consistently blunted by the Ca(2+) chelator ethylene glycol tetraacetic acid; neocortical Ca(2+) levels were significantly higher in all six patients; no difference in AGC transport rates was found in isolated mitochondria from patients and controls following removal of the Ca(2+)-containing postmitochondrial supernatant. Expression of AGC1, the predominant AGC isoform in brain, and cytochrome c oxidase activity were both increased in autistic patients, indicating an activation of mitochondrial metabolism. Furthermore, oxidized mitochondrial proteins were markedly increased in four of the six patients. Variants of the AGC1-encoding SLC25A12 gene were neither correlated with AGC activation nor associated with autism-spectrum disorders in 309 simplex and 17 multiplex families, whereas some unaffected siblings may carry a protective gene variant. Therefore, excessive Ca(2+) levels are responsible for boosting AGC activity, mitochondrial metabolism and, to a more variable degree, oxidative stress in autistic brains. AGC and altered Ca(2+) homeostasis play a key interactive role in the cascade of signaling events leading to autism: their modulation could provide new preventive and therapeutic strategies.

Asunto(s)

Agrecanos/metabolismo , Calcio/metabolismo , Trastornos Generalizados del Desarrollo Infantil/genética , Trastornos Generalizados del Desarrollo Infantil/metabolismo , Homeostasis/fisiología , Adolescente , Agrecanos/genética , Ácido Aspártico/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Estudios de Casos y Controles , Quelantes/farmacología , Niño , Trastornos Generalizados del Desarrollo Infantil/patología , Preescolar , Ácido Egtácico/farmacología , Complejo IV de Transporte de Electrones/metabolismo , Salud de la Familia , Femenino , Regulación de la Expresión Génica/fisiología , Genotipo , Ácido Glutámico/metabolismo , Homeostasis/efectos de los fármacos , Humanos , Desequilibrio de Ligamiento , Masculino , Mitocondrias/metabolismo , Neocórtex/metabolismo , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Serotonina/sangre , Adulto Joven

RESUMEN

Protein kinase C enzymes play an important role in signal transduction, regulation of gene expression and control of cell division and differentiation. The fsI and betaII isoenzymes result from the alternative splicing of the PKCbeta gene (PRKCB1), previously found to be associated with autism. We performed a family-based association study in 229 simplex and 5 multiplex families, and a postmortem study of PRKCB1 gene expression in temporocortical gray matter (BA41/42) of 11 autistic patients and controls. PRKCB1 gene haplotypes are significantly associated with autism (P<0.05) and have the autistic endophenotype of enhanced oligopeptiduria (P<0.05). Temporocortical PRKCB1 gene expression was reduced on average by 35 and 31% for the PRKCB1-1 and PRKCB1-2 isoforms (P<0.01 and <0.05, respectively) according to qPCR. Protein amounts measured for the PKCbetaII isoform were similarly decreased by 35% (P=0.05). Decreased gene expression characterized patients carrying the 'normal' PRKCB1 alleles, whereas patients homozygous for the autism-associated alleles displayed mRNA levels comparable to those of controls. Whole genome expression analysis unveiled a partial disruption in the coordinated expression of PKCbeta-driven genes, including several cytokines. These results confirm the association between autism and PRKCB1 gene variants, point toward PKCbeta roles in altered epithelial permeability, demonstrate a significant downregulation of brain PRKCB1 gene expression in autism and suggest that it could represent a compensatory adjustment aimed at limiting an ongoing dysreactive immune process. Altogether, these data underscore potential PKCbeta roles in autism pathogenesis and spur interest in the identification and functional characterization of PRKCB1 gene variants conferring autism vulnerability.

Asunto(s)

Trastorno Autístico/genética , Trastorno Autístico/patología , Expresión Génica/genética , Predisposición Genética a la Enfermedad , Neocórtex/metabolismo , Proteína Quinasa C/genética , Adolescente , Adulto , Distribución de Chi-Cuadrado , Niño , Preescolar , Salud de la Familia , Femenino , Frecuencia de los Genes , Estudio de Asociación del Genoma Completo/métodos , Genotipo , Humanos , Masculino , Polimorfismo de Nucleótido Simple/genética , Proteína Quinasa C beta , Adulto Joven

RESUMEN

Organophosphates (OPs) are routinely used as pesticides in agriculture and as insecticides within the household. Our prior work on Reelin and APOE delineated a gene-environment interactive model of autism pathogenesis, whereby genetically vulnerable individuals prenatally exposed to OPs during critical periods in neurodevelopment could undergo altered neuronal migration, resulting in an autistic syndrome. Since household use of OPs is far greater in the USA than in Italy, this model was predicted to hold validity in North America, but not in Europe. Here, we indirectly test this hypothesis by assessing linkage/association between autism and variants of the paraoxonase gene (PON1) encoding paraoxonase, the enzyme responsible for OP detoxification. Three functional single nucleotide polymorphisms, PON1 C-108T, L55M, and Q192R, were assessed in 177 Italian and 107 Caucasian-American complete trios with primary autistic probands. As predicted, Caucasian-American and not Italian families display a significant association between autism and PON1 variants less active in vitro on the OP diazinon (R192), according to case-control contrasts (Q192R: chi2=6.33, 1 df, P<0.025), transmission/disequilibrium tests (Q192R: TDT chi2=5.26, 1 df, P<0.025), family-based association tests (Q192R and L55M: FBAT Z=2.291 and 2.435 respectively, P<0.025), and haplotype-based association tests (L55/R192: HBAT Z=2.430, P<0.025). These results are consistent with our model and provide further support for the hypothesis that concurrent genetic vulnerability and environmental OP exposure may possibly contribute to autism pathogenesis in a sizable subgroup of North American individuals.

Asunto(s)

Arildialquilfosfatasa/genética , Trastorno Autístico/enzimología , Trastorno Autístico/genética , Arildialquilfosfatasa/metabolismo , Trastorno Autístico/etiología , Secuencia de Bases , Estudios de Casos y Controles , Niño , ADN/genética , Análisis Mutacional de ADN , Ambiente , Femenino , Variación Genética , Humanos , Insecticidas/metabolismo , Italia , Desequilibrio de Ligamiento , Masculino , Modelos Biológicos , Organofosfatos/metabolismo , Péptidos/orina , Polimorfismo de Nucleótido Simple , Proteína Reelina , Serotonina/sangre , Estados Unidos

RESUMEN

Fragile X syndrome is an X-linked form of mental retardation including, among others, symptoms such as stereotypic behaviour, hyperactivity, hyperarousal, and cognitive deficits. We hypothesized that hyperactivity and/or compromised attentional, cognitive functions may lead to impaired performance in cognitive tasks in Fmr1 knockout mice, the most widely used animal model of fragile X syndrome, and suggested that psychostimulant treatment may improve performance by acting on one or both components. Since hyperactivity and cognitive functions have been suggested to depend on striatal and prefrontal cortex dopaminergic dysfunction, we assessed whether amphetamine produced beneficial, positive effects by acting on dopaminergic corticostriatal systems. Our results show that Fmr1 knockout mice are not able to discriminate between a familiar object and a novel one in the object recognition test, thus showing a clear-cut cognitive impairment that, to date, has been difficult to demonstrate in other cognitive tasks. Amphetamine improved performance of Fmr1 knockout mice, leading to enhanced ability to discriminate novel versus familiar objects, without significantly affecting locomotor activity. In agreement with behavioural data, amphetamine produced a greater increase in dopamine release in the prefrontal cortex of Fmr1 knockout compared with the wild-type mice, while a weak striatal dopaminergic response was observed in Fmr1 knockout mice. Our data support the view that the psychostimulant ameliorates performance in Fmr1 knockout mice by improving merely cognitive functions through its action on prefrontal cortical dopamine, irrespective of its action on motor hyperactivity. These results indicate that prefrontal cortical dopamine plays a major role in cognitive impairments characterizing Fmr1 knockout mice, thus pointing to an important aetiological factor in the fragile X syndrome.

Asunto(s)

Anfetamina/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Dopamina/farmacología , Síndrome del Cromosoma X Frágil/fisiopatología , Proteínas del Tejido Nervioso/genética , Corteza Prefrontal/fisiología , Proteínas de Unión al ARN/genética , Reconocimiento en Psicología/efectos de los fármacos , Animales , Trastornos del Conocimiento/genética , Aprendizaje Discriminativo , Dopamina/metabolismo , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil , Síndrome del Cromosoma X Frágil/genética , Discapacidad Intelectual , Masculino , Ratones , Ratones Noqueados

RESUMEN

We have previously described linkage/association between reelin gene polymorphisms and autistic disorder. APOE also participates in the Reelin signaling pathway, by competitively antagonizing Reelin binding to APOE receptor 2 and to very-low-density lipoprotein receptors. The APOE2 protein variant displays the lowest receptor binding affinity compared with APOE3 and APOE4. In this study, we assess linkage/association between primary autism and APOE alleles in 223 complete trios, from 119 simplex Italian families and 44 simplex and 29 multiplex Caucasian-American families. Statistically significant disequilibrium favors the transmission of epsilon2 alleles to autistic offspring, over epsilon3 and epsilon4 (allele-wise transmission/disequilibrium test [TDT], chi2 = 6.16, 2 degrees of freedom [d.f.], P<0.05; genotype-wise TDT, chi2 = 10.68, 3 d.f., P<0.05). A novel epsilon3r allele was also discovered in an autistic child and his mother. Autistic patients do not differ significantly from unaffected siblings (allele-wise TDT comparing autistic patients versus unaffected sibs, chi2 = 1.83, 2 d.f., P<0.40, not significant). The major limitation of this study consists of our small sample size of trios including one unaffected sibling, currently not possessing the statistical power necessary to conclusively discriminate a specific association of epsilon2 with autism, from a distorted segregation pattern characterized by enhanced epsilon2 transmission rates both to affected and unaffected offspring. Our findings are thus compatible with either (a) pathogenetic contributions by epsilon2 alleles to autism spectrum vulnerability, requiring additional environmental and/or genetic factors to yield an autistic syndrome, and/or (b) a protective effect of epsilon2 alleles against the enhanced risk of miscarriage and infertility previously described among parents of autistic children.

Asunto(s)

Apolipoproteínas E/genética , Trastorno Autístico/genética , Apolipoproteína E2 , Apolipoproteína E3 , Apolipoproteína E4 , Secuencia de Bases , Cartilla de ADN , Familia , Genotipo , Humanos , Desequilibrio de Ligamiento , Proteína Reelina , Población Blanca

RESUMEN

Clinical and preclinical research suggests a major role of mesocortical dopamine (DA) in psychopathology through regulation of subcortical, especially mesoaccumbens, DA functioning. In these experiments we demonstrate that the high vulnerability to stress-induced 'despair' and mesoaccumbens DA inhibition, exhibited by mice of the inbred strain C57BL/6 (C57) in a common animal model of depression, depends on their being highly susceptible to stress-induced mesocortical DA activation. Thus, C57 mice but not mice of the DBA/2 strain showed an extremely high level of immobility on their first experience with the forced swimming test (FST) as well as immediate and strong activation of mesocortical DA metabolism and inhibition of mesoaccumbens DA metabolism and release. In addition, the behavioral and the mesoaccumbens DA responses to FST in C57 mice were reduced and reversed, respectively, by bilateral mesocortical DA depletion. Finally, chronic treatment with the antidepressant clomipramine reduced immobility and eliminated both mesocortical DA activation and mesoaccumbens DA inhibition in response to FST. These results suggest that a genetically determined susceptibility to stress by the mesocortical DA system may favor the development of pathological behavioral responses through inhibition of subcortical DA transmission.

Asunto(s)

Trastorno Depresivo/genética , Dopamina/deficiencia , Vías Nerviosas/metabolismo , Núcleo Accumbens/metabolismo , Corteza Prefrontal/metabolismo , Estrés Fisiológico/genética , Animales , Antidepresivos Tricíclicos/farmacología , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Clomipramina/farmacología , Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/metabolismo , Modelos Animales de Enfermedad , Predisposición Genética a la Enfermedad/genética , Genotipo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Actividad Motora/efectos de los fármacos , Actividad Motora/genética , Inhibición Neural/efectos de los fármacos , Inhibición Neural/genética , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/fisiopatología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/fisiopatología , Oxidopamina , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/fisiopatología , Estrés Fisiológico/metabolismo , Estrés Fisiológico/fisiopatología

RESUMEN

Autism is a biologically-heterogeneous disease. Distinct subgroups of autistic patients may be marked by intermediate phenotypes, such as elevated serotonin (5-HT) blood levels, potentially associated with different underlying disease mechanisms. This could lead to inconsistent genetic association results, such as those of prior studies on serotonin transporter (5-HTT) gene promoter variants and autistic disorder. Contributions of 5-HTT gene promoter alleles to 5-HT blood levels were thus investigated in 134 autistic patients and 291 first-degree relatives. Mean 5-HT blood levels are 11% higher in autistic patients carrying the L/L genotype, compared to patients with the S/S or S/L genotype; this trend is not observed in first-degree relatives. The probability of inheriting L or S alleles is significantly enhanced in patients with 5-HT blood levels above or below the mean, respectively (P < 0.05), but quantitative TDT analyses yield a non-significant trend (P = 0.10), as this polymorphism explains only 2.5% of the variance in 5-HT blood levels of autistic patients. In conclusion, 5-HTT gene promoter variants seemingly exert a small effect on 5-HT blood levels in autistic children, which largely does not account for hyperserotoninemia. Nonetheless, the inconsistent outcome of prior association studies could partly stem from a selection bias of hyper- or hypo-serotoninemic probands.

Asunto(s)

Trastorno Autístico/sangre , Trastorno Autístico/genética , Proteínas Portadoras/genética , Glicoproteínas de Membrana/genética , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso , Serotonina/sangre , Niño , Salud de la Familia , Femenino , Variación Genética , Haplotipos , Humanos , Desequilibrio de Ligamiento , Masculino , Regiones Promotoras Genéticas/genética , Proteínas de Transporte de Serotonina en la Membrana Plasmática

RESUMEN

Attention-deficit hyperactivity disorder (ADHD) is a highly prevalent childhood psychiatric disorder characterized by impaired attention, excessive motor activity and impulsivity. Converging evidence, suggests a primary role of disturbances in brain dopamine (DA) transmission and a role of genetic factors in its pathology. Inbred provide a well-defined and stable genotype for analysis. C57BL/6 (C57) and DBA/2 (DBA) mice are amongst the most studied inbred strains in the behavioral pharmacology of DA, and they differ in several parameters of the DA system that relate directly to behavioral differences. These strains also exhibit several qualitatively different behavior patterns that rely on separate DA networks (e.g. mesoaccumbens vs. nigrostriatal) and on different modes of inheritance. C57 mice are good learners in most tasks also involving associative learning but are totally unable to learn active avoidance although being very active. Moreover, C57 mice show greater novelty-induced locomotor activity than DBA, which is modulated strongly by DA neurons in the ventral tegmental area (VTA) region. Pharmacological studies also indicate a facilitated mesoaccumbens DA transmission in C57 mice when compared to DBAs. Increased density of D2 autoreceptors located on VTA neurons, and lower D2 postsynaptic receptors in the NAS were observed in DBA relative to C57. Activation of D2 autoreceptors inhibits impluse flow, synthesis, and release rates of DA neurons. As would be predicted from their higher D2 autoreceptor: DBA compared to C57 mice show reduced DA synthesis and release within the mesoaccumbens DA system when challenged with DA direct agonists. However, DBA mice are by fare more susceptible than C57s to stress-induced enhanced mesoaccumbens DA release and in stressful situation, they show sustained active behavioral responses whilst C57 adopt extremely passive responses (behavioral despair). Finally, chronic or repeated stress promote opposite adaptation of VTA DA autoreceptors in the two strains and render the hypoactive DBAs as active as the C57 mice. These results indicate that a complex interaction between genetic and environmental factors controls, mesoaccumbens DA functioning and hyperactive phenotype.

Asunto(s)

Trastorno por Déficit de Atención con Hiperactividad/genética , Ratones Endogámicos/genética , Ratones Endogámicos/psicología , Animales , Trastorno por Déficit de Atención con Hiperactividad/psicología , Conducta Animal/fisiología , Química Encefálica/genética , Química Encefálica/fisiología , Ratones , Fenotipo , Especificidad de la Especie