El cerebelo en el Autismo

Autism is considered as a neurodevelopmental disorder which affects boys more than girls, in a proportion 4:1 respectively. Autism presents neuroanatomical abnormalities located in the frontal cortex, the amygdala and the cerebellum. Autistic cerebellar postmortem studies have revealed a reduced number of Purkinje cells as well as a reduced Purkinje cell size when compared with non-autistic subjects. These anatomical alterations compromise the role of the cerebellum in cognitive, motor, emotional, learning and memory neural processes resulting in a different interpretation of the world, and therefore a different way to respond and behave. There are both biological and environmental insults causing the behavioral and neuroanatomical autistic phenotype. Valproic acid, an antiepileptic drug, has been related to some autistic cases after mothers were under medication with this drug during the first trimester of gestation and given birth autistic children. Therefore, in this brief review we analyzed the most recent advances of autism research in humans, with a primary focus on the use of valproic acid as a teratogen that mimics in rats some of the neuroanatomical alterations seen in autistic humans. In addition to the peculiar cerebellar pathology, all of this to shed light on a better understating of this disorder.El autismo es un trastorno generalizado del desarrollo que afecta más a varones que mujeres, con una proporción de 4 a 1, respectivamente. Dentro de sus características neuropatológicas más sobresalientes se encuentran la alteración anatómica de diversas estructuras del sistema nervioso central como la corteza frontal, la amígdala y el cerebelo. Estudios post mórtem en cerebelos de sujetos autistas han mostrado una notable disminución en el número de neuronas de Purkinje así como en su tamaño, comparado con las de sujetos sanos. Estas alteraciones anatómicas comprometen la participación del cerebelo en los procesos neurales como la cognición, actividad motora, la emoción, el aprendizaje y la memoria, dando como resultado una interpretación diferente del mundo que impacta sobre la respuesta y el comportamiento de los sujetos autistas. Actualmente se desconoce la causa de estas alteraciones anatómicas y aunque se avanza rápido en la ciencia se tiene la limitante de los sujetos experimentales, que en este caso son humanos. Por lo tanto, en esta revisión analizamos los hallazgos más relevantes de la patología cerebelar en el autismo, así como el uso del ácido valproico en ratas como teratógeno para simular alteraciones cerebelares como las observadas en autistas, contribuyendo a un mejor entendimiento de su neuropatología

Prenatal exposure to sodium valproate alters androgen receptor expression in the developing cerebellum in a region and age specific manner in male and female rats

Valproic acid (VPA) is an anti-epileptic drug with teratogenicity activity that has been related to autism. In rodents, exposure to VPA in utero leads to brain abnormalities similar than those reported in the autistic brain. Particularly, VPA reduces the number of Purkinje neurons in the rat cerebellum parallel to cerebellar abnormalities found in autism. Thus, we injected pregnant females on embryonic day 12 either with VPA (600 mg/kg, i.p.) or 0.9% saline solution and obtained the cerebellum from their offspring at different postnatal time points. Testosterone has been linked to autism and plays an important role during brain development. Therefore, we identified and analyzed the androgen receptor (AR) by immunohistochemistry and densitometry, respectively. We found VPA decreases AR density in the superficial Purkinje layer only in cerebellar lobule 8 at PN7, but increased it at PN14 compared to control in males. In females, VPA decreased AR density in the superficial Purkinje layer in cerebellar lobule 6 at PN14, but increased it in lobule 9 at the same time point. No differences were found in the deep Purkinje layer of any cerebellar lobule in terms of AR density neither in males nor females. We additionally found a particular AR density decreasing in both superficial and deep regions across development in the majority of cerebellar lobules in males, but in all cerebellar lobules in females. Thus, our results indicate that VPA disrupts the AR ontogeny in the developing cerebellum in an age and region specific manner in male and female rats. Future epigenetic studies including the evaluation of histone deacetylases (HDAC’s) might shed light these results as HDAC’s are expressed by Purkinje neurons, interact with the AR and are VPA targets. This work contributes to the understanding of the cerebellar development and it might help to understand the role of the cerebellum in neurodevelopmental disorders such as autism.This research was supported by CONACYT (Consejo Nacional de Ciencia y Tecnologia of Mexico Grant 106531 to Maria Elena Hernandez (MEH) and CONACYT Doctorate scholarship 205779 to Miguel Perez Pouchoulen (MPP). Authors thank M.S. Dulce Mariely Alvarez-Croda for her valuable comments to the manuscript

Characterization of four types of tail abnormalities in rats treated prenatally with valproic acid

Valproic acid (VPA) is an anticonvulsant drug used mainly for the treatment of epilepsy, bipolar disorder and schizophrenia. The VPA has been shown to be a potent teratogen that causes birth defects and malformations. Likewise, there are reports that suggest a relationship between the use of VPA during pregnancy and an increased incidence of children with neurological disorders such as autism. In humans, prenatal exposure to VPA produces malformations including dimorphic facial features suggestive of a lesion in the neural tube, as in the case of spina bifida, heart disease, limb defects and craniofacial anomalies as well as genital abnormalities. Herein we describe four tail abnormalities found in rats treated prenatally with valproic acid, which has been used as an animal model for the study of autistic features. These malformations may be associated with neural damage, but further studies are needed in order to correlate each tail abnormality with the kind of neural alterationEl ácido valpróico (AVP) es un fármaco anticonvulsivo usado principalmente para el tratamiento de la epilepsia, trastorno bipolar y esquizofrenia. Se ha demostrado que el AVP es un teratógeno potente que causa defectos de nacimiento y malformaciones. Así mismo, hay informes que sugieren una relación entre el uso de AVP durante el embarazo y un aumento de la incidencia de niños con trastornos neurológicos tales como el espectro autista. En los seres humanos, la exposición prenatal a la AVP produce malformaciones que sugieren un defecto durante el cierre del tubo neural, como es el caso de la espina bífida, enfermedades del corazón, defectos de las extremidades, anomalías craneofaciales, así como anomalías genitales. En el presente trabajo se describen cuatro anormalidades de la cola en ratas tratadas prenatalmente con ácido valpróico. Este tratamiento se ha utilizado como modelo animal para el estudio de rasgos autistas. Estas malformaciones pudieran estar asociadas con algún daño en el sistema nervioso, sin embargo se requieren más estudios para correlacionar cada anormalidad de la cola con el tipo de alteración neura

Microglia Morphological Categorization in a Rat Model of Neuroinflammation by Hierarchical Cluster and Principal Components Analysis

It is known that microglia morphology and function are closely related, but only few studies have objectively described different morphological subtypes. To address this issue, morphological parameters of microglial cells were analyzed in a rat model of aseptic neuroinflammation. After the injection of a single dose of the enzyme neuraminidase (NA) within the lateral ventricle (LV) an acute inflammatory process occurs. Sections from NA-injected animals and sham controls were immunolabeled with the microglial marker IBA1, which highlights ramifications and features of the cell shape. Using images obtained by section scanning, individual microglial cells were sampled from various regions (septofimbrial nucleus, hippocampus and hypothalamus) at different times post-injection (2, 4 and 12 h). Each cell yielded a set of 15 morphological parameters by means of image analysis software. Five initial parameters (including fractal measures) were statistically different in cells from NA-injected rats (most of them IL-1β positive, i.e., M1-state) compared to those from control animals (none of them IL-1β positive, i.e., surveillant state). However, additional multimodal parameters were revealed more suitable for hierarchical cluster analysis (HCA). This method pointed out the classification of microglia population in four clusters. Furthermore, a linear discriminant analysis (LDA) suggested three specific parameters to objectively classify any microglia by a decision tree. In addition, a principal components analysis (PCA) revealed two extra valuable variables that allowed to further classifying microglia in a total of eight sub-clusters or types. The spatio-temporal distribution of these different morphotypes in our rat inflammation model allowed to relate specific morphotypes with microglial activation status and brain location. An objective method for microglia classification based on morphological parameters is proposed.Main pointsMicroglia undergo a quantifiable morphological change upon neuraminidase induced inflammation.Hierarchical cluster and principal components analysis allow morphological classification of microglia.Brain location of microglia is a relevant factor