RESUMEN
After a spinal cord injury, axons fail to regenerate in the adult mammalian central nervous system, leading to permanent deficits in sensory and motor functions. Increasing neuronal activity after an injury using electrical stimulation or rehabilitation can enhance neuronal plasticity and result in some degree of recovery; however, the underlying mechanisms remain poorly understood. We found that placing mice in an enriched environment before an injury enhanced the activity of proprioceptive dorsal root ganglion neurons, leading to a lasting increase in their regenerative potential. This effect was dependent on Creb-binding protein (Cbp)-mediated histone acetylation, which increased the expression of genes associated with the regenerative program. Intraperitoneal delivery of a small-molecule activator of Cbp at clinically relevant times promoted regeneration and sprouting of sensory and motor axons, as well as recovery of sensory and motor functions in both the mouse and rat model of spinal cord injury. Our findings showed that the increased regenerative capacity induced by enhancing neuronal activity is mediated by epigenetic reprogramming in rodent models of spinal cord injury. Understanding the mechanisms underlying activity-dependent neuronal plasticity led to the identification of potential molecular targets for improving recovery after spinal cord injury.
Asunto(s)
Axones/fisiología , Proteína de Unión a CREB/metabolismo , Ambiente , Histonas/metabolismo , Regeneración Nerviosa , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/fisiopatología , Acetilación , Animales , Calcio/metabolismo , Modelos Animales de Enfermedad , Proteína p300 Asociada a E1A/metabolismo , Ganglios Espinales/patología , Ganglios Espinales/fisiopatología , Ratones , Neuronas Motoras/patología , Propiocepción , Recuperación de la Función , Células Receptoras Sensoriales/patología , Transducción de Señal , Traumatismos de la Médula Espinal/patologíaRESUMEN
The development of inhibitory circuits depends on the action of a network of transcription factors and epigenetic regulators that are critical for interneuron specification and differentiation. Although the identity of many of these transcription factors is well established, much less is known about the specific contribution of the chromatin-modifying enzymes that sculpt the interneuron epigenome. Here, we generated a mouse model in which the lysine acetyltransferase CBP is specifically removed from neural progenitors at the median ganglionic eminence (MGE), the structure where the most abundant types of cortical interneurons are born. Ablation of CBP interfered with the development of MGE-derived interneurons in both sexes, causing a reduction in the number of functionally mature interneurons in the adult forebrain. Genetic fate mapping experiments not only demonstrated that CBP ablation impacts on different interneuron classes, but also unveiled a compensatory increment of interneurons that escaped recombination and cushion the excitatory-inhibitory imbalance. Consistent with having a reduced number of interneurons, CBP-deficient mice exhibited a high incidence of spontaneous epileptic seizures, and alterations in brain rhythms and enhanced low gamma activity during status epilepticus. These perturbations led to abnormal behavior including hyperlocomotion, increased anxiety and cognitive impairments. Overall, our study demonstrates that CBP is essential for interneuron development and the proper functioning of inhibitory circuitry in vivo.
Asunto(s)
Diferenciación Celular/genética , Epigénesis Genética , Interneuronas/citología , Eminencia Media/citología , Proteínas de la Membrana/metabolismo , Fosfoproteínas/metabolismo , Potenciales de Acción , Animales , Ansiedad/complicaciones , Ansiedad/fisiopatología , Conducta Animal , Mapeo Cromosómico , Trastornos del Conocimiento/complicaciones , Trastornos del Conocimiento/fisiopatología , Epilepsia/complicaciones , Epilepsia/patología , Epilepsia/fisiopatología , Femenino , Hipocampo/metabolismo , Interneuronas/metabolismo , Ácido Kaínico , Aprendizaje , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Parvalbúminas/metabolismo , Somatostatina/metabolismo , Factor Nuclear Tiroideo 1/metabolismoRESUMEN
During development, chromatin-modifying enzymes regulate both the timely establishment of cell-type-specific gene programs and the coordinated repression of alternative cell fates. To dissect the role of one such enzyme, the intellectual-disability-linked lysine demethylase 5C (Kdm5c), in the developing and adult brain, we conducted parallel behavioral, transcriptomic, and epigenomic studies in Kdm5c-null and forebrain-restricted inducible knockout mice. Together, genomic analyses and functional assays demonstrate that Kdm5c plays a critical role as a repressor responsible for the developmental silencing of germline genes during cellular differentiation and in fine-tuning activity-regulated enhancers during neuronal maturation. Although the importance of these functions declines after birth, Kdm5c retains an important genome surveillance role preventing the incorrect activation of non-neuronal and cryptic promoters in adult neurons.
Asunto(s)
Regulación del Desarrollo de la Expresión Génica , Neuronas/metabolismo , Oxidorreductasas N-Desmetilantes/genética , Prosencéfalo/metabolismo , Transcripción Genética , Animales , Proteínas de Unión al ADN , Proteínas de Dominio Doblecortina , Elementos de Facilitación Genéticos , Femenino , Proteína Ácida Fibrilar de la Glía/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Histona Demetilasas , Histonas/genética , Histonas/metabolismo , Masculino , Aprendizaje por Laberinto , Ratones , Ratones Noqueados , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/patología , Neuropéptidos/genética , Neuropéptidos/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Oxidorreductasas N-Desmetilantes/deficiencia , Prosencéfalo/patología , Transducción de SeñalRESUMEN
The current view of neuroplasticity depicts the changes in the strength and number of synaptic connections as the main physical substrate for behavioral adaptation to new experiences in a changing environment. Although transcriptional regulation is known to play a role in these synaptic changes, the specific contribution of activity-induced changes to both the structure of the nucleus and the organization of the genome remains insufficiently characterized. Increasing evidence indicates that plasticity-related genes may work in coordination and share architectural and transcriptional machinery within discrete genomic foci. Here we review the molecular and cellular mechanisms through which neuronal nuclei structurally adapt to stimuli and discuss how the perturbation of these mechanisms can trigger behavioral malfunction.