RESUMEN

Down syndrome (DS) is the most frequent genetic cause of mental retardation. Cognitive dysfunction in these patients is correlated with reduced dendritic branching and complexity, along with fewer spines of abnormal shape that characterize the cortical neuronal profile of DS. DS phenotypes are caused by the disruptive effect of specific trisomic genes. Here, we report that overexpression of dual-specificity tyrosine phosphorylation-regulated kinase 1A, DYRK1A, is sufficient to produce the dendritic alterations observed in DS patients. Engineered changes in Dyrk1A gene dosage in vivo strongly alter the postnatal dendritic arborization processes with a similar progression than in humans. In cultured mammalian cortical neurons, we determined a reduction of neurite outgrowth and synaptogenesis. The mechanism underlying neurite dysgenesia involves changes in the dynamic reorganization of the cytoskeleton.

Asunto(s)

Corteza Cerebral/metabolismo , Citoesqueleto/metabolismo , Síndrome de Down/metabolismo , Neurogénesis , Neuronas/metabolismo , Neuronas/patología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Animales , Corteza Cerebral/patología , Citoesqueleto/patología , Síndrome de Down/patología , Ratones , Ratones Transgénicos , Quinasas DyrK

RESUMEN

The ability to flexibly adapt to the changing demands of the environment is often reported as a core deficit in fragile X syndrome (FXS). However, the cognitive processes that determine this attentional set-shifting deficit remain elusive. The present study investigated attentional set-shifting ability in fragile X syndrome males with the well-validated intra/extra dimensional set-shifting paradigm (IED) which offers detailed assessment of rule learning, reversal learning, and attentional set-shifting ability within and between stimulus dimensions. A novel scoring method for IED stage errors was employed to interpret set-shifting failure in terms of repetitive decision-making, distraction to irrelevance, and set-maintenance failure. Performance of FXS males was compared to typically developing children matched on mental age, adults matched on chronological age, and individuals with Down syndrome matched on both mental and chronological age. Results revealed that a significant proportion of FXS males already failed prior to the intra-dimensional set-shift stage, whereas all control participants successfully completed the stages up to the crucial extra-dimensional set-shift. FXS males showed a specific weakness in reversal learning, which was characterized by repetitive decision-making during the reversal of newly acquired stimulus-response associations in the face of simple stimulus configurations. In contrast, when stimulus configurations became more complex, FXS males displayed increased distraction to irrelevant stimuli. These findings are interpreted in terms of the cognitive demands imposed by the stages of the IED in relation to the alleged neural deficits in FXS.

Asunto(s)

Atención/fisiología , Síndrome del Cromosoma X Frágil/psicología , Aprendizaje Inverso/fisiología , Disposición en Psicología , Adulto , Cognición/fisiología , Toma de Decisiones/fisiología , Femenino , Humanos , Discapacidad Intelectual/psicología , Masculino , Pruebas Neuropsicológicas

RESUMEN

OBJECTIVE: This study examined whether attention deficits in fragile X syndrome (FXS) can be traced back to abnormalities in basic information processing. METHOD: Sixteen males with FXS and 22 age-matched control participants (mean age 29 years) performed a standard oddball task to examine selective attention in both auditory and visual modalities. Five FXS males were excluded from analysis because they performed below chance level on the auditory task. ERPs were recorded to investigate the N1, P2, N2b, and P3b components. RESULTS: N1 and N2b components were significantly enhanced in FXS males to both auditory and visual stimuli. Interestingly, in FXS males, the P3b to auditory stimuli was significantly reduced relative to visual stimuli. These modality differences in information processing corresponded to behavioral results, showing more errors on the auditory than on the visual task. CONCLUSIONS: The current findings suggest that attentional impairments in FXS at the behavioral level can be traced back to abnormalities in event-related cortical activity. These information processing abnormalities in FXS may hinder the allocation of attentional resources needed for optimal processing at higher-levels. SIGNIFICANCE: These findings demonstrate that auditory information processing in FXS males is critically impaired relative to visual information processing.

Asunto(s)

Atención/fisiología , Corteza Auditiva/fisiopatología , Síndrome del Cromosoma X Frágil/fisiopatología , Síndrome del Cromosoma X Frágil/psicología , Corteza Visual/fisiopatología , Estimulación Acústica , Adolescente , Adulto , Envejecimiento/fisiología , Percepción Auditiva/fisiología , Electroencefalografía , Potenciales Evocados/fisiología , Potenciales Evocados Auditivos/fisiología , Potenciales Evocados Visuales/fisiología , Síndrome del Cromosoma X Frágil/complicaciones , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Estimulación Luminosa , Desempeño Psicomotor/fisiología , Tiempo de Reacción/fisiología , Análisis de Regresión , Trastornos de la Sensación/etiología , Trastornos de la Sensación/fisiopatología , Trastornos de la Sensación/psicología , Percepción Visual/fisiología , Adulto Joven

RESUMEN

OBJECTIVE: The present study investigated involuntary change detection in a two-tone pre-attentive auditory discrimination paradigm in order to better understand the information processing mechanisms underlying attention deficits in fragile X syndrome (FXS) males. METHODS: Sixteen males with the FXS full mutation and 20 age-matched control participants (mean age 29 years) were presented with series of auditory stimuli consisting of standard and deviant tones while watching a silent movie. RESULTS: Brain potentials recorded to the tones showed that N1 and P2, sensory evoked potentials, were significantly enhanced in FXS compared to age-matched control participants. In contrast to controls, the N1 to standard tones failed to show long-term habituation to stimulus repetition in FXS. Additionally, both mismatch negativity and P3a generation, reflecting automatic change detection and the involuntary switch of attention, respectively, were significantly attenuated in FXS males. CONCLUSIONS: The current study demonstrates that auditory stimulus discrimination in the FXS brain is already compromised during the pre-attentive stages of information processing. Furthermore, the apparent pre-attentive information processing deficiencies in FXS coincide with a weakness in the involuntary engagement of attentional resources. SIGNIFICANCE: The stimulus-driven information processing deficiencies in FXS might compromise information processing in several domains and, thus, present a key-deficit in FXS neurocognition.

Asunto(s)

Umbral Auditivo/fisiología , Encéfalo/fisiopatología , Electroencefalografía , Potenciales Evocados Auditivos/fisiología , Síndrome del Cromosoma X Frágil/fisiopatología , Estimulación Acústica , Adolescente , Adulto , Trastorno por Déficit de Atención con Hiperactividad/fisiopatología , Mapeo Encefálico , Estudios de Casos y Controles , Humanos , Masculino , Persona de Mediana Edad , Discriminación de la Altura Tonal/fisiología , Tiempo de Reacción/fisiología , Adulto Joven

RESUMEN

The present study examined the cognitive profile in Fragile X Syndrome (FXS) males, and investigated whether cognitive profiles are similar for FXS males at different levels of intellectual functioning. Cognitive abilities in non-verbal, verbal, memory and executive functioning domains were contrasted to both a non-verbal and verbal mental age reference. Model-based cluster analyses revealed three distinct subgroups which differed in level of functioning, but showed similar cognitive profiles. Results showed that cognitive performance is particularly weak on measures of reasoning- and performal abilities confined to abstract item content, but relatively strong on measures of visuo-perceptual recognition and vocabulary. Further, a significant weakness was found for verbal short-term memory. Finally, these results indicated that the choice of an appropriate reference is critically important in examining cognitive profiles. The pattern of findings that emerged from the current cognitive profiling of FXS males was interpreted to suggest a fundamental deficit in executive control.

Asunto(s)

Trastornos del Conocimiento/fisiopatología , Función Ejecutiva , Síndrome del Cromosoma X Frágil/fisiopatología , Memoria a Corto Plazo , Reconocimiento Visual de Modelos , Adolescente , Adulto , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/psicología , Síndrome del Cromosoma X Frágil/diagnóstico , Síndrome del Cromosoma X Frágil/psicología , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/fisiopatología , Discapacidad Intelectual/psicología , Pruebas de Inteligencia , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Psicometría , Índice de Severidad de la Enfermedad , Conducta Verbal , Vocabulario , Adulto Joven

RESUMEN

To properly observe induced connectivity changes after training sessions, one needs a network model that describes individual relationships in sufficient detail to enable observation of induced changes and yet reveals some kind of stability in these relationships. We analyzed spontaneous firing activity in dissociated rat cortical networks cultured on multi-electrode arrays by means of the conditional firing probability. For all pairs (i, j) of the 60 electrodes, we calculated conditional firing probability (CFP(i,j)[tau]) as the probability of an action potential at electrode j at t = tau, given that one was detected at electrode i at t = 0. If a CFP(i,j)[tau] distribution clearly deviated from a flat one, electrodes i and j were considered to be related. For all related electrode pairs, a function was fitted to the CFP-curve to obtain parameters for 'strength' and 'delay' (i.e. maximum and latency of the maximum of the curve) of each relationship. In young cultures the set of identified relationships changed rather quickly. At 16 days in vitro (DIV) 50% of the set changed within 2 days. Beyond 25 DIV this set stabilized: during a week more than 50% of the set remained intact. Most individual relationships developed rather gradually. Moreover, beyond 25 DIV relational strength appeared quite stable, with coefficients of variation (100 x SD/mean) around 25% in periods of approximately 10 h. CFP analysis provides a robust method to describe the underlying probabilistic structure of highly varying spontaneous activity in cultured cortical networks. It may offer a suitable basis for plasticity studies, in the case of changes in the probabilistic structure. CFP analysis monitors all pairs of electrodes instead of just a selected one. Still, it is likely to describe the network in sufficient detail to detect subtle changes in individual relationships.

Asunto(s)

Potenciales de Acción/fisiología , Relojes Biológicos/fisiología , Modelos Neurológicos , Modelos Estadísticos , Red Nerviosa/fisiología , Neuronas/fisiología , Animales , Animales Recién Nacidos , Células Cultivadas , Simulación por Computador , Ratas , Ratas Wistar

RESUMEN

Mental retardation (MR) is a developmental brain disorder characterized by impaired cognitive performance and adaptive skills that affects 1-2% of the population. During the last decade, a large number of genes have been cloned that cause MR upon mutation in humans. The causal role of these genes provides an excellent starting point to investigate the cellular, neurobiological and behavioral alterations and mechanisms responsible for the cognitive impairment in mentally retarded persons. However, studies on Down syndrome (DS) reveal that overexpression of a cluster of genes and various forms of MR that are caused by single-gene mutations, such as fragile X (FraX), Rett, Coffin-Lowry, Rubinstein-Taybi syndrome and non-syndromic forms of MR, causes similar phenotypes. In spite of the many differences in the manifestation of these forms of MR, evidence converges on the proposal that MR is primarily due to deficiencies in neuronal network connectivity in the major cognitive centers in the brain, which secondarily results in impaired information processing. Although MR has been largely regarded as a brain disorder that cannot be cured, our increased understanding of the abnormalities and mechanisms underlying MR may provide an avenue for the development of therapies for MR. In this review, we discuss the neurobiology underlying MR, with a focus on FraX and DS.

Asunto(s)

Dendritas/patología , Síndrome de Down/genética , Síndrome del Cromosoma X Frágil/genética , Discapacidad Intelectual/genética , Vías Nerviosas/patología , Animales , Dendritas/genética , Modelos Animales de Enfermedad , Síndrome de Down/complicaciones , Síndrome de Down/patología , Síndrome del Cromosoma X Frágil/complicaciones , Síndrome del Cromosoma X Frágil/patología , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad , Humanos , Discapacidad Intelectual/etiología , Discapacidad Intelectual/patología , Ratones , Proteínas del Tejido Nervioso/genética , Vías Nerviosas/citología , Vías Nerviosas/fisiopatología , Fenotipo

RESUMEN

Recently, the polyglutamine-binding protein 1 (PQBP1) gene was found to be mutated in five of 29 families studied with X-linked mental retardation (XLMR) linked to Xp. The reported mutations include duplications or deletions of AG dinucleotides in the fourth coding exon that resulted in shifts of the open reading frame. Three of the five families with mutations in this newly identified XLMR gene have been reported previously. We characterized the phenotypic and neuropsychological features in the two unpublished families with aberrations in PQBP1 and in a family reported 10 years ago. In total, seven patients diagnosed with aberrations in this gene were examined, including a newly identified patient at 18 months of age. Additionally, the features were compared to those reported in the literature of three other families, comprising MRXS3 (Sutherland-Haan syndrome) MRX55 and MRXS8 (Renpenning syndrome). Characteristics seen in these patients are microcephaly, lean body habitus, short stature, striking facial appearance with long narrow faces, upward slant of the eyes, malar hypoplasia, prognathism, high-arched palate and nasal speech. In addition, small testes and midline defects as anal atresia or imperforate anus, clefting of palate and/or uvula, iris coloboma and Tetralogy of Fallot are seen in several patients. These observations contribute to the phenotypic knowledge of patients with PQBP1 mutations and make this XLMR syndrome well recognizable to clinicians.

Asunto(s)

Proteínas Portadoras/genética , Discapacidad Intelectual Ligada al Cromosoma X/genética , Mutación/genética , Proteínas Nucleares/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Proteínas de Unión al ADN , Familia , Femenino , Ligamiento Genético , Genotipo , Humanos , Lactante , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Síndrome

RESUMEN

Spontaneous action potentials were recorded longitudinally for 4-7 weeks from dissociated rat occipital cortex cells cultured on planar multi-electrode plates, during their development from isolated neurons into synaptically connected neuronal networks. Activity typically consisted of generalized bursts lasting up to several seconds, separated by variable epochs of sporadic firing at some of the active sites. These network bursts displayed discharge patterns with age-dependent firing rate profiles, and durations significantly increasing in the 3rd week in vitro and decreasing after about 1 month in vitro, when they evolved into short events with prompt onsets. These findings indicate that after about a month in vitro these cultured neuronal networks have developed a degree of excitability that allows almost instantaneous triggering of generalized discharges. Individual neurons tend to fire in specific and persistent temporal relationships to one another within these network bursts, suggesting that network connectivity maintains a core topology during its development.

Asunto(s)

Potenciales de Acción/fisiología , Diferenciación Celular/fisiología , Red Nerviosa/fisiología , Vías Nerviosas/fisiología , Neuronas/fisiología , Corteza Visual/fisiología , Animales , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Microelectrodos , Red Nerviosa/citología , Red Nerviosa/embriología , Vías Nerviosas/citología , Vías Nerviosas/embriología , Neuronas/citología , Ratas , Sinapsis/fisiología , Transmisión Sináptica/fisiología , Corteza Visual/citología , Corteza Visual/embriología

RESUMEN

Chronic blockade of bioelectric activity (BEA) has been shown to increase neuronal cell death in tissue culture, but the effects of this treatment on non-neuronal cells have not been investigated. To determine which cell types are affected by chronic suppression of BEA, we investigated their morphological development in primary cultures of rat cerebral cortex, grown with or without the sodium channel blocker tetrodotoxin (TTX). Morphological development was monitored by phase-contrast microscopy and by immunofluorescent staining of markers specific for neurons (NSE, MAP2, B-50, and the 200 kD neurofilament protein), astrocytes (GFAP), oligodendrocytes (galactocerebroside), macrophages (ED-1) and fibroblasts (fibronectin). Neurons in control cultures steadily increased in size and elaborated a dense network of axons and dendrites during the first 3 weeks. Astrocytes proliferated strongly and formed a 'bottom-layer' on which other cells grew. Part of the astrocytes migrated into the peripheral area of the culture, but retracted to the centre after 14 days in vitro (DIV). Oligodendrocytes and macrophages also increased in number, but oligodendrocytes were completely lost by 28 DIV. After 3 weeks, axons that had grown into the periphery of the culture gradually retracted and/or degenerated, following the retracting astrocytes. Some of the neurons died after 21 DIV, but a large part persisted until 42 DIV. Upon TTX treatment from 5/6 DIV, cultures with few macrophages showed an increase in the proportion of necrotic nuclei at 14 and 21 DIV. The retraction of peripherally located fibres was accelerated by 3 - 4 days and their degeneration was augmented. Neuronal density decreased to zero between 21 and 42 DIV. Astrocytes showed a clear decrease in density from 28 DIV. Conversely, the density of macrophages was increased about two-fold from 14 DIV. These results indicate that both neurons and glia are affected by chronic TTX treatment.

RESUMEN

Chronic suppression of spontaneously occurring bioelectric activity (BEA) has been shown to increase neuronal cell death in tissue culture, but may also affect astrocytes. We investigated this process in primary cultures of rat cerebral cortex by measuring the levels of NSE (neuron-specific enolase) and GFAP (glial fibrillary acidic protein) in relation to general tissue markers, including measurements for cell death and proliferation. In electrically active (control) cultures, the content of DNA, protein, and NSE became maximal between 21 and 28 days in vitro (DIV) and thereafter decreased, whereas the content of GFAP rose continuously up to 43 DIV. Chronic suppression of BEA by tetrodotoxin (TTX; from 6 DIV) decreased the content of DNA, total protein, and especially NSE. The content of GFAP was decreased in all culture series investigated, but with great temporal variations among culture series. Chronic TTX treatment (started at 6 DIV) increased the efflux of lactate dehydrogenase, a marker for cell lysis, between 12 and 21 DIV, but this efflux was mainly derived from the supporting glial cells with which the cerebral cortex cultures were cocultured. Chronic, but not acute (7 h) TTX treatment decreased total [3H]thymidine incorporation into DNA from 14 DIV; this appeared to be due to a reduced number of astrocytes. Chronic suppression of BEA with xylocaine from 6 DIV had similar effects on DNA-, protein-, and NSE-content as TTX, but led to an increased content of GFAP at 21 DIV. Chronic suppression of synaptic transmission with 10 mM Mg2+ and 0.2 mM Ca2+, starting at 6 DIV, increased the content of DNA, protein, and GFAP at 21 DIV, but NSE was still decreased. We conclude that chronic suppression of BEA in cerebral cortex cultures enhances neuronal cell death, whereas astrocytes are differentially affected, depending on the suppressing agent. As astrocytes may have a modulating effect on neuronal survival, their involvement should be regarded when studying the effects of chronic suppression of BEA on neuronal development.