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 DyrKRESUMEN
The consumption of drugs of abuse provokes sensitization, the development of tolerance, dependency, and eventually addiction. It is thought that these events are partially a consequence of drug-induced alterations in the organization of neuronal circuits in specific areas of the brain. In the present study, we have used intracellular injections of lucifer yellow to examine the alterations that may occur in cortical pyramidal neurons of addiction-prone Lewis rats following 15 days of self-administration of morphine. Specifically, the effects of morphine on the structure, size and branching complexity of the basal dendrites, and spine density were determined in the basal dendritic arbors of layer III pyramidal neurons in both the prelimbic and motor cortex. We found that following morphine self-administration, there was a reduction in the size and branching complexity of the dendritic arbors of pyramidal cells in the motor cortex. In contrast, prelimbic pyramidal neurons from these morphine-treated animals had larger and longer basal dendritic arbors. Furthermore, the spine density on pyramidal neurons was higher in both cortical regions of morphine self-administered rats. These results suggest that at least part of the behavioral changes produced by repeated opiate administration may be attributed to alterations in pyramidal cell structure.
Asunto(s)
Analgésicos Opioides/farmacología , Corteza Cerebral/patología , Dependencia de Morfina/genética , Dependencia de Morfina/patología , Morfina/farmacología , Células Piramidales/patología , Analgésicos Opioides/administración & dosificación , Animales , Colorantes Fluorescentes , Isoquinolinas , Sistema Límbico/patología , Masculino , Morfina/administración & dosificación , Corteza Motora/patología , Ratas , Ratas Endogámicas Lew , AutoadministraciónRESUMEN
Dendritic spines of pyramidal cells are the main postsynaptic targets of cortical excitatory synapses and as such, they are fundamental both in neuronal plasticity and for the integration of excitatory inputs to pyramidal neurons. There is significant variation in the number and density of dendritic spines among pyramidal cells located in different cortical areas and species, especially in primates. This variation is believed to contribute to functional differences reported among cortical areas. In this study, we analyzed the density of dendritic spines in the motor, somatosensory and visuo-temporal regions of the mouse cerebral cortex. Over 17,000 individual spines on the basal dendrites of layer III pyramidal neurons were drawn and their morphologies compared among these cortical regions. In contrast to previous observations in primates, there was no significant difference in the density of spines along the dendrites of neurons in the mouse. However, systematic differences in spine dimensions (spine head size and spine neck length) were detected, whereby the largest spines were found in the motor region, followed by those in the somatosensory region and those in visuo-temporal region.
Asunto(s)
Espinas Dendríticas/ultraestructura , Neocórtex/ultraestructura , Animales , Espinas Dendríticas/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Neocórtex/fisiología , Plasticidad Neuronal , Células Piramidales/fisiología , Células Piramidales/ultraestructuraRESUMEN
The gene encoding the dual-specificity tyrosine-regulated kinase DYRK1A maps to the chromosomal segment HSA21q22.2, which lies within the Down syndrome critical region. The reduction in brain size and behavioral defects observed in mice lacking one copy of the murine homologue Dyrk1A (Dyrk1A+/-) support the idea that this kinase may be involved in monosomy 21 associated mental retardation. However, the structural basis of these behavioral defects remains unclear. In the present work, we have analyzed the microstructure of cortical circuitry in the Dyrk1A+/- mouse and control littermates by intracellular injection of Lucifer Yellow in fixed cortical tissue. We found that labeled pyramidal cells were considerably smaller, less branched and less spinous in the cortex of Dyrk1A+/- mice than in control littermates. These results suggest that Dyrk1A influences the size and complexity of pyramidal cells, and thus their capability to integrate information.
Asunto(s)
Neocórtex/anomalías , Neocórtex/patología , Malformaciones del Sistema Nervioso/genética , Proteínas Serina-Treonina Quinasas/genética , Células Piramidales/patología , Animales , Diferenciación Celular/genética , Forma de la Célula/genética , Espinas Dendríticas/metabolismo , Espinas Dendríticas/patología , Modelos Animales de Enfermedad , Síndrome de Down/genética , Síndrome de Down/patología , Síndrome de Down/fisiopatología , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neocórtex/metabolismo , Malformaciones del Sistema Nervioso/metabolismo , Malformaciones del Sistema Nervioso/patología , Fenotipo , Proteínas Tirosina Quinasas , Células Piramidales/metabolismo , Quinasas DyrKRESUMEN
Recent studies have revealed systematic differences in the pyramidal cell structure between functionally related cortical areas of primates. Trends for a parallel in pyramidal cell structure and functional complexity have been reported in visual, somatosensory, motor, cingulate and prefrontal cortex in the macaque monkey cortex. These specializations in structure have been interpreted as being fundamental in determining cellular and systems function, endowing circuits in these different cortical areas with different computational power. In the present study we extend our initial finding of systematic specialization of pyramidal cell structure in sensory-motor cortex in the macaque monkey [Cereb Cortex 12 (2002) 1071] to the vervet monkey. More specifically, we investigated pyramidal cell structure in somatosensory and motor areas 1/2, 5, 7, 4 and 6. Neurones in fixed, flat-mounted, cortical slices were injected intracellularly with Lucifer Yellow and processed for a light-stable 3,3'-diaminobenzidine reaction product. The size of, number of branches in, and spine density of the basal dendritic arbors varied systematically such that there was a trend for increasing complexity in arbor structure with progression through 1/2, 5 and 7. In addition, cells in area 6 were larger, more branched, and more spinous than those in area 4.
Asunto(s)
Corteza Motora/citología , Células Piramidales/citología , Corteza Somatosensorial/citología , Animales , Recuento de Células , Forma de la Célula , Tamaño de la Célula , Chlorocebus aethiops , Espinas Dendríticas , Indoles/metabolismo , MasculinoRESUMEN
Since the discovery in the 1970s that dendritic abnormalities in cortical pyramidal neurons are the most consistent pathologic correlate of mental retardation, research has focused on how dendritic alterations are related to reduced intellectual ability. Due in part to obvious ethical problems and in part to the lack of fruitful methods to study neuronal circuitry in the human cortex, there is little data about the microanatomical contribution to mental retardation. The recent identification of the genetic bases of some mental retardation associated alterations, coupled with the technology to create transgenic animal models and the introduction of powerful sophisticated tools in the field of microanatomy, has led to a growth in the studies of the alterations of pyramidal cell morphology in these disorders. Studies of individuals with Down syndrome, the most frequent genetic disorder leading to mental retardation, allow the analysis of the relationships between cognition, genotype and brain microanatomy. In Down syndrome the crucial question is to define the mechanisms by which an excess of normal gene products, in interaction with the environment, directs and constrains neural maturation, and how this abnormal development translates into cognition and behaviour. In the present article we discuss mainly Down syndrome-associated dendritic abnormalities and plasticity and the role of animal models in these studies. We believe that through the further development of such approaches, the study of the microanatomical substrates of mental retardation will contribute significantly to our understanding of the mechanisms underlying human brain disorders associated with mental retardation.
Asunto(s)
Trastornos del Conocimiento/patología , Trastornos del Conocimiento/fisiopatología , Dendritas/efectos de los fármacos , Dendritas/patología , Síndrome de Down/patología , Síndrome de Down/fisiopatología , Plasticidad Neuronal/efectos de los fármacos , Animales , Trastornos del Conocimiento/tratamiento farmacológico , Modelos Animales de Enfermedad , Síndrome de Down/tratamiento farmacológico , Síndrome de Down/genética , Terapia Genética/métodos , Humanos , Ratones , Neuronas/efectos de los fármacos , Neuronas/patologíaRESUMEN
Mental retardation in individuals with Down syndrome (DS) is thought to result from anomalous development and function of the brain; however, the underlying neuropathological processes have yet to be determined. Early implementation of special care programs result in limited, and temporary, cognitive improvements in DS individuals. In the present study, we investigated the possible neural correlates of these limited improvements. More specifically, we studied cortical pyramidal cells in the frontal cortex of Ts65Dn mice, a partial trisomy of murine chromosome 16 (MMU16) model characterized by cognitive deficits, hyperactivity, behavioral disruption and reduced attention levels similar to those observed in DS, and their control littermates. Animals were raised either in a standard or in an enriched environment. Environmental enrichment had a marked effect on pyramidal cell structure in control animals. Pyramidal cells in environmentally enriched control animals were significantly more branched and more spinous than non-enriched controls. However, environmental enrichment had little effect on pyramidal cell structure in Ts65Dn mice. As each dendritic spine receives at least one excitatory input, differences in the number of spines found in the dendritic arbors of pyramidal cells in the two groups reflect differences in the number of excitatory inputs they receive and, consequently, complexity in cortical circuitry. The present results suggest that behavioral deficits demonstrated in the Ts65Dn model could be attributed to abnormal circuit development.
Asunto(s)
Síndrome de Down/patología , Neocórtex/crecimiento & desarrollo , Neocórtex/patología , Células Piramidales/crecimiento & desarrollo , Células Piramidales/patología , Animales , Dendritas/patología , Modelos Animales de Enfermedad , Síndrome de Down/fisiopatología , Ambiente , Femenino , Ratones , Ratones Mutantes , Morfogénesis , Neocórtex/fisiopatología , Embarazo , Células Piramidales/fisiopatología , Valores de ReferenciaRESUMEN
Brain development and function are dependent on thyroid hormone (T3), which acts through nuclear hormone receptors. T3 receptors (TRs) are transcription factors that activate or suppress target gene expression in a hormone-dependent or -independent fashion. Two distinct genes, TRalpha and TRbeta, encode several receptor isoforms with specific functions defined in many tissues but not in the brain. Mutations in the TRbeta gene cause the syndrome of peripheral resistance to thyroid hormone; however, no alterations of the TRalpha gene have been described in humans. Here we demonstrate that mice lacking the TRalpha1 isoform display behavioral abnormalities of hippocampal origin, as shown by the open field and fear conditioning tests. In the open field test mutant mice revealed less exploratory behavior than wild-type mice. In the contextual fear conditioning test mutant mice showed a significantly higher freezing response than wild-type controls when tested 1 week after training. These findings correlated with fewer GABAergic terminals on the CA1 pyramidal neurons in the mutant mice. Our results indicate that TRalpha1 is involved in the regulation of hippocampal structure and function, and raise the possibility that deletions or mutations of this receptor isoform may lead to behavioral changes or even psychiatric syndromes in humans.
Asunto(s)
Conducta Animal/fisiología , Hipocampo/fisiología , Receptores alfa de Hormona Tiroidea/genética , Animales , Condicionamiento Psicológico/fisiología , Miedo/fisiología , Hipocampo/química , Hipocampo/citología , Interneuronas/química , Interneuronas/fisiología , Masculino , Memoria/fisiología , Ratones , Ratones Endogámicos BALB C , Ratones Mutantes , Inhibición Neural/fisiología , Parvalbúminas/análisis , Células Piramidales/química , Células Piramidales/fisiología , Receptores alfa de Hormona Tiroidea/análisis , Hormonas Tiroideas/análisis , Ácido gamma-Aminobutírico/fisiologíaRESUMEN
Here we present evidence that the pyramidal cell phenotype varies markedly in the cortex of different anthropoid species. Regional and species differences in the size of, number of bifurcations in, and spine density of the basal dendritic arbors cannot be explained by brain size. Instead, pyramidal cell morphology appears to accord with the specialized cortical function these cells perform. Cells in the prefrontal cortex of humans are more branched and more spinous than those in the temporal and occipital lobes. Moreover, cells in the prefrontal cortex of humans are more branched and more spinous than those in the prefrontal cortex of macaque and marmoset monkeys. These results suggest that highly spinous, compartmentalized, pyramidal cells (and the circuits they form) are required to perform complex cortical functions such as comprehension, perception, and planning.