RESUMEN
Subcortical band heterotopia (SBH), also known as doublecortex syndrome, is a malformation of cortical development resulting from mutations in the doublecortin gene (DCX). It is characterized by a lack of migration of cortical neurons that accumulate in the white matter forming a heterotopic band. Patients with SBH may present mild to moderate intellectual disability as well as epilepsy. The SBH condition can be modeled in rats by in utero knockdown (KD) of Dcx. The affected cells form an SBH reminiscent of that observed in human patients and the animals develop a chronic epileptic condition in adulthood. Here, we investigated if the presence of a SBH is sufficient to induce cognitive impairment in juvenile Dcx-KD rats, before the onset of epilepsy. Using a wide range of behavioral tests, we found that the presence of SBH did not appear to affect motor control or somatosensory processing. In addition, cognitive abilities such as learning, short-term and long-term memory, were normal in pre-epileptic Dcx-KD rats. We suggest that the SBH presence is not sufficient to impair these behavioral functions.
Asunto(s)
Conducta Animal , Lisencefalias Clásicas y Heterotopias Subcorticales en Banda/psicología , Cognición , Modelos Animales de Enfermedad , Epilepsia/genética , Discapacidad Intelectual/genética , Animales , Ansiedad/genética , Enfermedades Asintomáticas , Movimiento Celular , Lisencefalias Clásicas y Heterotopias Subcorticales en Banda/complicaciones , Lisencefalias Clásicas y Heterotopias Subcorticales en Banda/embriología , Lisencefalias Clásicas y Heterotopias Subcorticales en Banda/genética , Proteínas de Dominio Doblecortina , Proteína Doblecortina , Electroporación , Conducta Exploratoria , Sustancia Gris/anomalías , Sustancia Gris/embriología , Aprendizaje , Aprendizaje por Laberinto , Memoria , Proteínas Asociadas a Microtúbulos/deficiencia , Proteínas Asociadas a Microtúbulos/genética , Mosaicismo , Neuropéptidos/deficiencia , Neuropéptidos/genética , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/toxicidad , Ratas , Prueba de Desempeño de Rotación con Aceleración Constante , Sensación , Sustancia Blanca/anomalías , Sustancia Blanca/embriologíaRESUMEN
The neocortex is a 6-layered laminated structure with a precise anatomical and functional organization ensuring proper function. Laminar positioning of cortical neurons, as determined by termination of neuronal migration, is a key determinant of their ability to assemble into functional circuits. However, the exact contribution of laminar placement to dendrite morphogenesis and synapse formation remains unclear. Here we manipulated the laminar position of cortical neurons by knocking down doublecortin (Dcx), a crucial effector of migration, and show that misplaced neurons fail to properly form dendrites, spines, and functional glutamatergic and GABAergic synapses. We further show that knocking down Dcx in properly positioned neurons induces similar but milder defects, suggesting that the laminar misplacement is the primary cause of altered neuronal development. Thus, the specific laminar environment of their fated layers is crucial for the maturation of cortical neurons, and influences their functional integration into developing cortical circuits.