RESUMEN

The Reelin signaling pathway is implicated in processes controlling synaptic plasticity and hippocampus-dependent learning and memory. A single direct in vivo application of Reelin enhances long-term potentiation, increases dendritic spine density and improves associative and spatial learning and memory. Angelman syndrome (AS) is a neurological disorder that presents with an overall defect in synaptic function, including decreased long-term potentiation, reduced dendritic spine density, and deficits in learning and memory, making it an attractive model in which to examine the ability of Reelin to recover synaptic function and cognitive deficits. In this study, we investigated the effects of Reelin administration on synaptic plasticity and cognitive function in a mouse model of AS and demonstrated that bilateral, intraventricular injections of Reelin recover synaptic function and corresponding hippocampus-dependent associative and spatial learning and memory. Additionally, we describe alteration of the Reelin profile in tissue from both the AS mouse and post-mortem human brain.

Asunto(s)

Síndrome de Angelman/fisiopatología , Síndrome de Angelman/psicología , Moléculas de Adhesión Celular Neuronal/administración & dosificación , Proteínas de la Matriz Extracelular/administración & dosificación , Hipocampo/efectos de los fármacos , Potenciación a Largo Plazo/efectos de los fármacos , Proteínas del Tejido Nervioso/administración & dosificación , Serina Endopeptidasas/administración & dosificación , Síndrome de Angelman/tratamiento farmacológico , Animales , Moléculas de Adhesión Celular Neuronal/metabolismo , Corteza Cerebral/metabolismo , Espinas Dendríticas/efectos de los fármacos , Modelos Animales de Enfermedad , Proteínas de la Matriz Extracelular/metabolismo , Femenino , Células HEK293 , Hipocampo/fisiopatología , Hipocampo/ultraestructura , Humanos , Inyecciones Intraventriculares , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Proteínas del Tejido Nervioso/metabolismo , Proteína Reelina , Serina Endopeptidasas/metabolismo , Aprendizaje Espacial/efectos de los fármacos , Memoria Espacial/efectos de los fármacos

RESUMEN

Our understanding of biological mechanisms and treatment options for traumatic brain injury (TBI) is limited. Here, we employed quantitative real-time PCR (QRT-PCR) and immunohistochemical analyses to determine the dynamic expression of cell proliferation and apoptosis in an effort to provide insights into the therapeutic window for developing regenerative strategies for TBI. For this purpose, young adult Sprague-Dawley rats were subjected to experimental TBI using a controlled cortical impactor, then euthanized 1-48 hours after TBI for QRT-PCR and immunohistochemistry. QRT-PCR revealed that brains from TBI exposed rats initially displayed nestin mRNA expression that modestly increased as early as 1-hour post-TBI, then significantly peaked at 8 hours, but thereafter reverted to pre-TBI levels. On the other hand, caspase-3 mRNA expression was slightly elevated at 8 hours post-TBI, which did not become significantly upregulated until 48 hours. Immunofluorescent microscopy revealed a significant surge in nestin immunoreactive cells in the cortex, corpus callosum, and subventricular zone at 24 hours post-TBI, whereas a significant increase in the number of active caspase-3 immunoreactive cells was only found in the cortex and not until 48 hours. These results suggest that the injured brain attempts to repair itself via cell proliferation immediately after TBI, but that this endogenous regenerative mechanism is not sufficient to abrogate the secondary apoptotic cell death. Treatment strategies designed to amplify cell proliferation and to prevent apoptosis are likely to exert maximal benefits when initiated at the acute phase of TBI.