RESUMEN
BACKGROUND: GNAO1-related encephalopathies include a broad spectrum of developmental disorders caused by de novo heterozygous mutations in the GNAO1 gene, encoding the G (o) subunit α of G-proteins. These conditions are characterized by epilepsy, movement disorders and developmental impairment, in combination or as isolated features. OBJECTIVE: This study aimed at describing the profile of neurovisual competences in children with GNAO1 deficiency to better characterize the phenotype of the disease spectrum. METHODS: Four male and three female patients with confirmed genetic diagnosis underwent neurological examination, visual function assessment, and neurovisual and ophthalmological evaluation. Present clinical history of epilepsy and movement disorders, and neuroimaging findings were also evaluated. RESULTS: The assessment revealed two trends in visual development. Some aspects of visual function, such as discrimination and perception of distance, depth and volume, appeared to be impaired at all ages, with no sign of improvement. Other aspects, reliant on temporal lobe competences (ventral stream) and more related to object-face exploration, recognition and environmental control, appeared to be preserved and improved with age. SIGNIFICANCE: Visual function is often impaired, with patterns of visual impairment affecting the ventral stream less.
Asunto(s)
Discapacidades del Desarrollo , Subunidades alfa de la Proteína de Unión al GTP Gi-Go , Percepción Visual , Femenino , Humanos , Masculino , Encefalopatías/complicaciones , Encefalopatías/genética , Discapacidades del Desarrollo/complicaciones , Discapacidades del Desarrollo/genética , Epilepsia/genética , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/genética , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/metabolismo , Heterocigoto , Trastornos del Movimiento/genética , Fenotipo , Percepción Visual/genéticaRESUMEN
Photoreceptors in the vertebrate eye are dependent on the retinal pigmented epithelium for a variety of functions including retinal re-isomerization and waste disposal. The light-sensitive pineal gland of fish, birds, and amphibians is evolutionarily related to the eye but lacks a pigmented epithelium. Thus, it is unclear how these functions are performed. Here, we ask whether a subpopulation of zebrafish pineal cells, which express glial markers and visual cycle genes, is involved in maintaining photoreceptors. Selective ablation of these cells leads to a loss of pineal photoreceptors. Moreover, these cells internalize exorhodopsin that is secreted by pineal rod-like photoreceptors, and in turn release CD63-positive extracellular vesicles (EVs) that are taken up by pdgfrb-positive phagocytic cells in the forebrain meninges. These results identify a subpopulation of glial cells that is critical for pineal photoreceptor survival and indicate the existence of cells in the forebrain meninges that receive EVs released by these pineal cells and potentially function in waste disposal.
Asunto(s)
Neuroglía , Células Fotorreceptoras de Vertebrados , Glándula Pineal , Percepción Visual , Animales , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Expresión Génica , Melatonina , Meninges/citología , Meninges/fisiología , Neuroglía/citología , Neuroglía/metabolismo , Células Fotorreceptoras/citología , Células Fotorreceptoras/metabolismo , Células Fotorreceptoras de Vertebrados/metabolismo , Células Fotorreceptoras de Vertebrados/fisiología , Glándula Pineal/citología , Glándula Pineal/metabolismo , Rodopsina/metabolismo , Tetraspanina 30/metabolismo , Percepción Visual/genética , Percepción Visual/fisiología , Pez Cebra/genética , Pez Cebra/metabolismoRESUMEN
Schizophrenia is a severe psychiatric disorder determined by a complex mixture of genetic and environmental factors. To better understand the contributions of human genetic variations to schizophrenia, we performed a genome-wide association study (GWAS) of a highly sensitive endophenotype. In this visual masking endophenotype, two vertical bars, slightly shifted in the horizontal direction, are briefly presented (vernier offset). Participants are asked to indicate the offset direction of the bars (either left or right). The bars are followed by a grating mask, which makes the task both spatially and temporally challenging. The inter-stimulus interval (ISI) between the vernier and the mask was determined in 206 patients with schizophrenia, 109 first-order relatives, and 143 controls. Usually, in GWAS studies, patients are compared to controls (i.e., a binary task) without considering the large differences in performance between patients and controls, as it occurs in many paradigms. The masking task allows for a particularly powerful analysis because the differences in ISI within the patient population are large. We genotyped all participants and searched for associations between human polymorphisms and the masking endophenotype using a linear mixed model. We did not identify any genome-wide significant associations (p < 5 × 10-8), indicating that common variants with strong effects are unlikely to contribute to the large inter-group differences in visual masking. However, we found significant differences in polygenetic risk scores (PRS) between patients and controls, and relatives and controls.
Asunto(s)
Esquizofrenia , Humanos , Esquizofrenia/genética , Enmascaramiento Perceptual , Endofenotipos , Estudio de Asociación del Genoma Completo , Genotipo , Percepción Visual/genéticaRESUMEN
The Reelin gene (RELN) encodes a large extracellular protein, which has multiple roles in brain development and adult brain function. It activates a series of neuronal signal transduction pathways in the adult brain that function in synaptic plasticity, dendritic morphology, and cognitive function. To further investigate the roles of Reln in brain function, we generated a mouse line using the C57BL/6 J strain with the specific Reln deletion identified from a Japanese patient with schizophrenia (Reln-del mice). These mice exhibited abnormal sociality, but the pathophysiological significance of the Reln deletion for higher brain functions, such as learning and behavioral flexibility remains unclear. In this study, cognitive function in Reln-del mice was assessed using touchscreen-based visual discrimination (VD) and reversal learning (RL) tasks. Reln-del mice showed normal learning in the simple VD task, but the learning was delayed in the complex VD task as compared to their wild-type (WT) littermates. In the RL task, sessions were divided into early perseverative phase (sessions with <50% correct) and later learning phase (sessions with ≥50% correct). Reln-del mice showed normal perseveration but impaired relearning ability in both simple RL and complex RL task as compared to WT mice. These results suggest that Reln-del mice have impaired learning ability, but the behavioral flexibility is unaffected. Overall, the observed behavioral abnormalities in Reln-del mice suggest that this mouse model is a useful preclinical tool for investigating the neurobiological mechanism underlying cognitive impairments in schizophrenia and a therapeutic strategy.
Asunto(s)
Aprendizaje Discriminativo/fisiología , Proteína Reelina/genética , Aprendizaje Inverso/fisiología , Esquizofrenia/genética , Percepción Visual/genética , Animales , Cognición/fisiología , Modelos Animales de Enfermedad , Eliminación de Gen , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/metabolismoRESUMEN
The Drosophila visual system supports complex behaviors and shares many of its anatomical and molecular features with the vertebrate brain. Yet, it contains a much more manageable number of neurons and neuronal types. In addition to the extensive Drosophila genetic toolbox, this relative simplicity has allowed decades of work to yield a detailed account of its neuronal type diversity, morphology, connectivity and specification mechanisms. In the past three years, numerous studies have applied large scale single-cell transcriptomic approaches to the Drosophila visual system and have provided access to the complete gene expression profile of most neuronal types throughout development. This makes the fly visual system particularly well suited to perform detailed studies of the genetic mechanisms underlying the evolution and development of neuronal systems. Here, we highlight how these transcriptomic resources allow exploring long-standing biological questions under a new light. We first present the efforts made to characterize neuronal diversity in the Drosophila visual system and suggest ways to further improve this description. We then discuss current advances allowed by the single-cell datasets, and envisage how these datasets can be further leveraged to address fundamental questions regarding the regulation of neuronal identity, neuronal circuit development and the evolution of neuronal diversity.
Asunto(s)
Visión Ocular/genética , Percepción Visual/genética , Animales , Encéfalo/metabolismo , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Expresión Génica/genética , Perfilación de la Expresión Génica/métodos , Regulación del Desarrollo de la Expresión Génica/genética , Neurogénesis , Neuronas/metabolismo , Análisis de la Célula Individual/métodos , Transcriptoma/genética , Visión Ocular/fisiología , Percepción Visual/fisiologíaRESUMEN
Opioid peptides and their receptors are expressed in the mammalian retina; however, little is known about how they might affect visual processing. The melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs), which mediate important non-image-forming visual processes such as the pupillary light reflex (PLR), express ß-endorphin-preferring, µ-opioid receptors (MORs). The objective of the present study was to elucidate if opioids, endogenous or exogenous, modulate pupillary light reflex (PLR) via MORs expressed by ipRGCs. MOR-selective agonist [D-Ala2, MePhe4, Gly-ol5]-enkephalin (DAMGO) or antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) was administered via intravitreal injection. PLR was recorded in response to light stimuli of various intensities. DAMGO eliminated PLR evoked by light with intensities below melanopsin activation threshold but not that evoked by bright blue irradiance that activated melanopsin signaling, although in the latter case, DAMGO markedly slowed pupil constriction. CTAP or genetic ablation of MORs in ipRGCs slightly enhanced dim-light-evoked PLR but not that evoked by a bright blue stimulus. Our results suggest that endogenous opioid signaling in the retina contributes to the regulation of PLR. The slowing of bright light-evoked PLR by DAMGO is consistent with the observation that systemically applied opioids accumulate in the vitreous and that patients receiving chronic opioid treatment have slow PLR.
Asunto(s)
Péptidos Opioides/genética , Receptores Opioides mu/genética , Retina/metabolismo , Percepción Visual/genética , Animales , Encefalina Ala(2)-MeFe(4)-Gli(5)/farmacología , Encefalinas/antagonistas & inhibidores , Encefalinas/genética , Humanos , Luz , Ratones , Péptidos/farmacología , Receptores Opioides/genética , Receptores Opioides mu/antagonistas & inhibidores , Reflejo/genética , Retina/patología , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/fisiología , Transducción de Señal/efectos de los fármacos , Percepción Visual/efectos de los fármacos , betaendorfina/genéticaRESUMEN
Faces can be categorized in various ways, for example as male or female or as belonging to a specific biogeographic ancestry (race). Here we tested the importance of the main facial features for race perception. We exchanged inner facial features (eyes, mouth or nose), face contour (everything but those) or texture (surface information) between Asian and Caucasian faces. Features were exchanged one at a time, creating for each Asian/Caucasian face pair ten facial variations of the original face pair. German and Korean participants performed a race classification task on all faces presented in random order. The results show that eyes and texture are major determinants of perceived biogeographic ancestry for both groups of participants and for both face types. Inserting these features in a face of another race changed its perceived biogeographic ancestry. Contour, nose and mouth, in that order, had decreasing and much weaker influence on race perception for both participant groups. Exchanging those features did not induce a change of perceived biogeographic ancestry. In our study, all manipulated features were imbedded in natural looking faces, which were shown in an off-frontal view. Our findings confirm and extend previous studies investigating the importance of various facial features for race perception.
Asunto(s)
Cara/anatomía & histología , Reconocimiento Visual de Modelos/fisiología , Percepción Visual/fisiología , Adulto , Análisis de Varianza , Pueblo Asiatico/clasificación , Pueblo Asiatico/genética , Ojo/anatomía & histología , Cara/fisiología , Femenino , Humanos , Masculino , Boca/anatomía & histología , Nariz/anatomía & histología , Percepción Visual/genética , Población Blanca/clasificación , Población Blanca/genética , Adulto JovenRESUMEN
Many animal species remain separate not because their individuals fail to produce viable hybrids but because they "choose" not to mate. However, we still know very little of the genetic mechanisms underlying changes in these mate preference behaviours. Heliconius butterflies display bright warning patterns, which they also use to recognize conspecifics. Here, we couple QTL for divergence in visual preference behaviours with population genomic and gene expression analyses of neural tissue (central brain, optic lobes and ommatidia) across development in two sympatric Heliconius species. Within a region containing 200 genes, we identify five genes that are strongly associated with divergent visual preferences. Three of these have previously been implicated in key components of neural signalling (specifically an ionotropic glutamate receptor and two regucalcins), and overall our candidates suggest shifts in behaviour involve changes in visual integration or processing. This would allow preference evolution without altering perception of the wider environment.
Asunto(s)
Mariposas Diurnas/fisiología , Genes de Insecto , Especiación Genética , Preferencia en el Apareamiento Animal , Percepción Visual/genética , Animales , Mariposas Diurnas/genética , Femenino , Regulación de la Expresión Génica , Flujo Génico , Genes de Insecto/genética , Genoma de los Insectos/genética , Masculino , Mutación , Sitios de Carácter Cuantitativo , Especificidad de la Especie , Simpatría , Alas de AnimalesRESUMEN
The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has been linked to multiple aspects of cognition. For example, in rodents, discrimination and reversal learning are altered by experimentally induced changes in brain serotonin levels, and reduced expression of the 5-HT2B receptor subtype in mice and humans is associated with decreased serotonergic tone and increased behavioral impulsivity. Serotonin modulates cognitive flexibility as well as fear and anxiety, but the specific contributions of 5-HT2B receptors to these behaviors is unknown. The current study assessed mice with partial Htr2b deletion for performance on a touchscreen-based pairwise visual discrimination and reversal learning task followed by a test of cued fear learning. Male Htr2b heterozygous mice (+/-) and littermate controls (+/+) were trained to discriminate between two visual stimuli presented on a touch-sensitive screen, one which predicted delivery of a 14-mg food pellet and the other which was not rewarded. Once discrimination performance criterion was attained, the stimulus-reward contingencies were reversed. Htr2b +/- mice were faster to reach discrimination criterion than +/+ controls, and made fewer errors. Htr2b +/- mice were also slower to make responses and collect rewards. Conversely, measures of reversal learning were not different between genotypes. Pavlovian cued fear conditioning was also normal in Htr2b +/-mice. These data demonstrate a selective improvement in touchscreen-based discrimination learning in mice with partial deletion of the 5-HT2B receptor, and provide further insight into the role of the 5-HT2B receptor in cognition.
Asunto(s)
Aprendizaje Discriminativo/fisiología , Eliminación de Gen , Receptor de Serotonina 5-HT2B/genética , Aprendizaje Inverso , Percepción Visual/genética , Animales , Cognición/fisiología , Condicionamiento Operante/fisiología , Discriminación en Psicología/fisiología , Masculino , RatonesRESUMEN
Sensory systems rely on neuromodulators, such as serotonin, to provide flexibility for information processing as stimuli vary, such as light intensity throughout the day. Serotonergic neurons broadly innervate the optic ganglia of Drosophila melanogaster, a widely used model for studying vision. It remains unclear whether serotonin modulates the physiology of interneurons in the optic ganglia. To address this question, we first mapped the expression patterns of serotonin receptors in the visual system, focusing on a subset of cells with processes in the first optic ganglion, the lamina. Serotonin receptor expression was found in several types of columnar cells in the lamina including 5-HT2B in lamina monopolar cell L2, required for spatiotemporal luminance contrast, and both 5-HT1A and 5-HT1B in T1 cells, whose function is unknown. Subcellular mapping with GFP-tagged 5-HT2B and 5-HT1A constructs indicated that these receptors localize to layer M2 of the medulla, proximal to serotonergic boutons, suggesting that the medulla neuropil is the primary site of serotonergic regulation for these neurons. Exogenous serotonin increased basal intracellular calcium in L2 terminals in layer M2 and modestly decreased the duration of visually induced calcium transients in L2 neurons following repeated dark flashes, but otherwise did not alter the calcium transients. Flies without functional 5-HT2B failed to show an increase in basal calcium in response to serotonin. 5-HT2B mutants also failed to show a change in amplitude in their response to repeated light flashes but other calcium transient parameters were relatively unaffected. While we did not detect serotonin receptor expression in L1 neurons, they, like L2, underwent serotonin-induced changes in basal calcium, presumably via interactions with other cells. These data demonstrate that serotonin modulates the physiology of interneurons involved in early visual processing in Drosophila.
Asunto(s)
Receptor de Serotonina 5-HT1B/genética , Receptores de Serotonina 5-HT1/genética , Receptores de Serotonina 5-HT2/genética , Neuronas Serotoninérgicas/metabolismo , Serotonina/metabolismo , Animales , Ritmo Circadiano/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Regulación de la Expresión Génica/genética , Interneuronas/metabolismo , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Neurotransmisores/genética , Receptores de Serotonina/genética , Serotonina/genética , Percepción Visual/genéticaRESUMEN
The retinas from Period 1 (Per1) and Period 2 (Per2) double-mutant mice (Per1-/-Per2Brdm1) display abnormal blue-cone distribution associated with a reduction in cone opsin mRNA and protein levels, up to 1 year of age. To reveal the molecular mechanisms by which Per1 and Per2 control retina development, we analyzed genome-wide gene expression differences between wild-type (WT) and Per1-/-Per2Brdm1 mice across ocular developmental stages (E15, E18 and P3). All clock genes displayed changes in transcript levels along with normal eye development. RNA-Seq data show major gene expression changes between WT and mutant eyes, with the number of differentially expressed genes (DEG) increasing with developmental age. Functional annotation of the genes showed that the most significant changes in expression levels in mutant mice involve molecular pathways relating to circadian rhythm signaling at E15 and E18. At P3, the visual cascade and the cell cycle were respectively higher and lower expressed compared to WT eyes. Overall, our study provides new insights into signaling pathways -phototransduction and cell cycle- controlled by the circadian clock in the eye during development.
Asunto(s)
Ciclo Celular/genética , Ojo/embriología , Ojo/metabolismo , Organogénesis/genética , Proteínas Circadianas Period/genética , Percepción Visual/genética , Alelos , Animales , Diferenciación Celular/genética , Biología Computacional/métodos , Perfilación de la Expresión Génica , Regulación del Desarrollo de la Expresión Génica , Genotipo , Ratones , Proteínas Circadianas Period/metabolismo , Transducción de Señal , TranscriptomaRESUMEN
Pit vipers possess a unique thermal sensory system consisting of facial pits that allow them to detect minute temperature fluctuations within their environments. Biologists have long attempted to elucidate the genetic basis underlying the infrared perception of pit vipers. Early studies have shown that the TRPA1 gene is the thermal sensor associated with infrared detection in pit vipers. However, whether genes other than TRPA1 are also involved in the infrared perception of pit vipers remains unknown. Here, we sequenced the whole exomes of ten snake species and performed genome-wide evolutionary analyses to search for novel candidate genes that might be involved in the infrared perception of pit vipers. We applied both branch-length-comparison and selection-pressure-alteration analyses to identify genes that specifically underwent accelerated evolution in the ancestral lineage of pit vipers. A total of 47 genes were identified. These genes were significantly enriched in the ion transmembrane transporter, stabilization of membrane potential, and temperature gating activity functional categories. The expression levels of these candidate genes in relevant nerve tissues (trigeminal ganglion, dorsal root ganglion, midbrain, and cerebrum) were also investigated in this study. We further chose one of our candidate genes, the potassium channel gene KCNK4, as an example to discuss its possible role in the infrared perception of pit vipers. Our study provides the first genome-wide survey of infrared perception-related genes in pit vipers via comparative evolutionary analyses and reveals valuable candidate genes for future functional studies.
Asunto(s)
Crotalinae/genética , Evolución Molecular , Secuenciación del Exoma , Estudios de Asociación Genética , Genoma , Rayos Infrarrojos , Percepción Visual/genética , Sustitución de Aminoácidos/genética , Animales , Encéfalo/metabolismo , Simulación por Computador , Regulación de la Expresión Génica , Ontología de Genes , Sistemas de Lectura Abierta/genética , Filogenia , Canales de Potasio/química , Canales de Potasio/genética , Selección GenéticaRESUMEN
We act upon stimuli in our surrounding environment by gathering the multisensory information they convey and by integrating this information to decide on a behavioral action. We hypothesized that the anterolateral secondary visual cortex (area AL) of the mouse brain may serve as a hub for sensorimotor transformation of audiovisual information. We imaged neuronal activity in primary visual cortex (V1) and AL of the mouse during a detection task using visual, auditory, and audiovisual stimuli. We found that AL neurons were more sensitive to weak uni- and multisensory stimuli compared to V1. Depending on contrast, different subsets of AL and V1 neurons showed cross-modal modulation of visual responses. During audiovisual stimulation, AL neurons showed stronger differentiation of behaviorally reported versus unreported stimuli compared to V1, whereas V1 showed this distinction during unisensory visual stimulation. Thus, neural population activity in area AL correlates more closely with multisensory detection behavior than V1.
Asunto(s)
Percepción Auditiva/genética , Neuronas/metabolismo , Estimulación Luminosa/métodos , Corteza Visual/fisiología , Percepción Visual/genética , Animales , Humanos , RatonesRESUMEN
Fragile X syndrome (FX), the most common inherited form of autism and intellectual disability, is a condition associated with visual perceptual learning deficits. We recently discovered that perceptual experience can encode visual familiarity via persistent low-frequency oscillations in the mouse primary visual cortex (V1). Here, we combine this paradigm with a multifaceted experimental approach to identify neurophysiological impairments of these oscillations in FX mice. Extracellular recordings reveal shorter durations, lower power, and lower frequencies of peak oscillatory activity in FX mice. Directed information analysis of extracellularly recorded spikes reveals differences in functional connectivity from multiple layers in FX mice after the perceptual experience. Channelrhodopsin-2 assisted circuit mapping (CRACM) reveals increased synaptic strength from L5 pyramidal onto L4 fast-spiking cells after experience in wild-type (WT), but not FX, mice. These results suggest differential encoding of visual stimulus familiarity in FX via persistent oscillations and identify circuit connections that may underlie these changes.
Asunto(s)
Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Corteza Visual/fisiología , Percepción Visual/fisiología , Animales , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Femenino , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuronas/metabolismo , Percepción Visual/genéticaRESUMEN
Perceptual experiences may arise from neuronal activity patterns in mammalian neocortex. We probed mouse neocortex during visual discrimination using a red-shifted channelrhodopsin (ChRmine, discovered through structure-guided genome mining) alongside multiplexed multiphoton-holography (MultiSLM), achieving control of individually specified neurons spanning large cortical volumes with millisecond precision. Stimulating a critical number of stimulus-orientation-selective neurons drove widespread recruitment of functionally related neurons, a process enhanced by (but not requiring) orientation-discrimination task learning. Optogenetic targeting of orientation-selective ensembles elicited correct behavioral discrimination. Cortical layer-specific dynamics were apparent, as emergent neuronal activity asymmetrically propagated from layer 2/3 to layer 5, and smaller layer 5 ensembles were as effective as larger layer 2/3 ensembles in eliciting orientation discrimination behavior. Population dynamics emerging after optogenetic stimulation both correctly predicted behavior and resembled natural internal representations of visual stimuli at cellular resolution over volumes of cortex.
Asunto(s)
Neocórtex/fisiología , Neocórtex/ultraestructura , Neuronas/fisiología , Percepción Visual/fisiología , Animales , Organismos Acuáticos/genética , Células Cultivadas , Channelrhodopsins/genética , Holografía/métodos , Ratones , Imagen Molecular , Opsinas/genética , Optogenética , Orientación/fisiología , Estimulación Luminosa , Percepción Visual/genéticaRESUMEN
The SNARE complex plays a crucial role in the synaptic exocytosis of neurotransmitters, a process involved in the Alzheimer's disease (AD), the most common form of dementia. SNAP-25, STX1a, and VAMP2 are the core proteins of the SNARE complex, and changes in protein level are suggested to contribute to cognitive impairment and neuropsychiatric disorders. Single nucleotide polymorphisms (SNPs) in SNARE complex genes were shown to be associated with different diseases and different cognitive impairments. Chi-square analysis was used to compare case-control difference of ApoE4, SNAP-25 rs363039, rs363043, rs363950, STX1a rs4717806, rs2293489, and VAMP2 26bp Ins/Del genotype distribution in 192 AD, 187 mild cognitive impairment (MCI), and 200 healthy controls (HC). Results of genotype and allelic distribution of SNAP-25 rs363050 showed that AA genotype (AD versus HC: pâ=â1.5×10-4; MCI versus HC: pâ=â8.7×10-3) as well as A allele (AD versus HC: pâ=â6.0×10-4; MCI versus HC: pâ=â5.7×10-3) are significantly more frequent in AD and MCI compared to HC. Genotype distribution of STX1a rs4717806 and rs2293489 resulted significantly different in AD compared to HC (pâ=â0.032 and pâ=â0.047, respectively). Moreover, distribution of the STX1a rs4717806 allele in SNAP-25 rs363050 AA carriers was significantly different between MCI and HC (pâ=â0.018). Notably, in MCI, visual selective attention impairment was associated with the STX1a rs4717806 AA (pcâ=â0.027) genotype as well as the SNAP-25/STX1a rs363050/rs4717806 AA/A (pcâ=â0.022) combination. These data suggest that SNPs in SNARE complex genes may interfere and/or modulate the activity of the SNARE complex resulting in impairments of neurotransmission that involve attention brain areas.
Asunto(s)
Enfermedad de Alzheimer/genética , Atención/fisiología , Proteínas SNARE/genética , Percepción Visual/genética , Anciano , Alelos , Enfermedad de Alzheimer/psicología , Apolipoproteína E4/genética , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Polimorfismo de Nucleótido SimpleRESUMEN
ARID1B mutations in Coffin-Siris syndrome are a cause of intellectual disability (0.5-1%), with various degrees of autism and agenesis of the corpus callosum (10%). Little is known regarding the cognitive and motor consequences of ARID1B mutations in humans and no link has been made between corpus callosum anomalies and visuospatial and neuromotor dysfunctions. We have investigated the visuospatial and neuromotor phenotype in eight patients with ARID1B mutations. A paramedian sagittal section of the brain MRI was selected, and corpus callosum was measured in anteroposterior length, genu and trunk width. Spearman's rank order coefficients were used to explore correlations between visuospatial and social cognitive variables and dimensions of the corpus callosum. A significant correlation between genu width size and visual cognition was observed. Retrocerebellar cysts were associated with corpus callosum anomalies. Here, we show that corpus callosum anomalies caused in ARID1B mutations may be predictive of the visuospatial and motor phenotype in Coffin-Siris syndrome.
Asunto(s)
Anomalías Múltiples/genética , Cuerpo Calloso/metabolismo , Proteínas de Unión al ADN/genética , Cara/anomalías , Deformidades Congénitas de la Mano/genética , Discapacidad Intelectual/genética , Micrognatismo/genética , Cuello/anomalías , Factores de Transcripción/genética , Adolescente , Trastorno del Espectro Autista/genética , Benchmarking , Niño , Preescolar , Proteínas de Unión al ADN/metabolismo , Familia , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Masculino , Mutación , Enfermedades Neuromusculares/genética , Pruebas Neuropsicológicas , Fenotipo , Factores de Transcripción/metabolismo , Percepción Visual/genética , Adulto JovenRESUMEN
A common feature of several psychiatric disorders is the attentional impairment. eEF2K -/- , IL1RAPL1 -/- and SHANK3Δ11 -/- mice were used as animal models consistently linked to changes in synaptic plasticity, learning and memory. All knockout (KO) mice and their corresponding littermates were submitted to the novel object recognition (NOR) and visual object recognition (VOR) tasks. In the NOR, eEF2K-/- mice exhibited a normal performance in terms of mean discrimination index, while SHANK3Δ11-/- and IL1RAPL1 -/- mice were impaired when a delay of 2 and 24 hours was introduced. Surprisingly, when submitted to VOR, where the two objects were replaced with two shapes delivered from two iPods, all the mutant mice performed worse than those in the NOR. In VOR, the application of motion to different shapes, to increase attention, improved performance in eEF2K -/- and IL1RAPL1 -/- but not in SHANK3Δ11 -/- mice. In SHANK3Δ11 -/- mice, attentional deficit was also present even if different motions were applied to the same shapes or when these mice were repeatedly exposed for 5 days to the context. Behavioral analysis showed that eEF2K-/- and IL1RAPL1 -/- mice had a good flexibility tested in the T-maze. eEF2K-/- showed normal self-grooming. On the basis of previous literature data indicating that SHANK3Δ11 -/- showed impaired flexibility and reduced sociability, we identified in this genotype the most exhaustive model showing all the core symptoms of autism spectrum disorder including a heavy visual attention deficit. These findings show the importance of VOR to identify mouse models of autism.
Asunto(s)
Atención , Quinasa del Factor 2 de Elongación/genética , Proteína Accesoria del Receptor de Interleucina-1/genética , Proteínas del Tejido Nervioso/genética , Percepción Visual/genética , Animales , Discriminación en Psicología , Eliminación de Gen , Aseo Animal , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas de Microfilamentos , Conducta SocialRESUMEN
Purpose: The rapid rise in prevalence over recent decades and high heritability of myopia suggest a role for gene-environment (G × E) interactions in myopia susceptibility. Few such G × E interactions have been discovered to date. We aimed to test the hypothesis that genetic analysis of susceptibility to visual experience-induced myopia in an animal model would identify novel G × E interaction loci. Methods: Chicks aged 7 days (n = 987) were monocularly deprived of form vision for 4 days. A genome-wide association study (GWAS) was carried out in the 20% of chicks most susceptible and least susceptible to form deprivation (n = 380). There were 304,963 genetic markers tested for association with the degree of induced axial elongation in treated versus control eyes (A-scan ultrasonography). A GWAS candidate region was examined in the following three human cohorts: CREAM consortium (n = 44,192), UK Biobank (n = 95,505), and Avon Longitudinal Study of Parents and Children (ALSPAC; n = 4989). Results: A locus encompassing the genes PIK3CG and PRKAR2B was genome-wide significantly associated with myopia susceptibility in chicks (lead variant rs317386235, P = 9.54e-08). In CREAM and UK Biobank GWAS datasets, PIK3CG and PRKAR2B were enriched for strongly-associated markers (meta-analysis lead variant rs117909394, P = 1.7e-07). In ALSPAC participants, rs117909394 had an age-dependent association with refractive error (-0.22 diopters [D] change over 8 years, P = 5.2e-04) and nearby variant rs17153745 showed evidence of a G × E interaction with time spent reading (effect size -0.23 D, P = 0.022). Conclusions: This work identified the PIK3CG-PRKAR2B locus as a mediator of susceptibility to visually induced myopia in chicks and suggests a role for this locus in conferring susceptibility to myopia in human cohorts.
Asunto(s)
Fosfatidilinositol 3-Quinasa Clase Ib/genética , Subunidad RIIbeta de la Proteína Quinasa Dependiente de AMP Cíclico/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/métodos , Miopía/genética , Percepción Visual/genética , Adolescente , Animales , Animales Recién Nacidos , Longitud Axial del Ojo/patología , Pollos , Niño , Bases de Datos Factuales , Modelos Animales de Enfermedad , Femenino , Interacción Gen-Ambiente , Técnicas de Genotipaje , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Privación SensorialRESUMEN
BACKGROUND: Vision plays a critical role in host location and oviposition behavior for herbivorous insects. However, the molecular mechanisms underlying visual regulation in host recognition and oviposition site selection in insects remains unknown. The aim of this study was to explore the key visual genes that are linked to the host plant location of the fruit fly, Bactrocera minax. RESULTS: Using a host specialist fruit fly, B. minax, which lays eggs only into immature green citrus fruit, we undertook behavioral, transcriptomic, and RNAi research to identify the molecular basis for host fruit color recognition. In laboratory and field assays we found that adults prefer green over other colors, and this preference is significantly increased in sexually mature over immature flies. Furthermore, we identified that the Rh6 gene, responsible for green spectral sensitivity, has elevated expression in mature flies over immature flies. RNAi suppression of Rh6 eliminated the preference for green, resulting in a significant decrease in the number of eggs laid by B. minax in green unripe citrus. CONCLUSION: These results show that the Rh6 gene modulates the visual mechanism of host utilization in B. minax, providing a genetic basis for visual host location in a non-model insect herbivore. © 2018 Society of Chemical Industry.