Mutations in the X-linked methyl-CpG binding protein 2 (Mecp2) gene cause the majority of Rett syndrome (RTT) cases, a neurological disorder that affects 1:10000-15000 girls worldwide. MeCP2 mouse mutants recapitulate many features found in human RTT. MeCP2 KO are characterized by a short life span, breathing defects, motor impairments, defects in basal synaptic transmission and plasticity and in neuronal formation. Hence, an accurate analysis of the mouse models represents an essential step towards the comprehension of the cause of RTT and is necessary for developing new therapies. Environmental enrichment (EE) is a housing conditions that facilitate enhanced sensory, cognitive, social and motor stimulation. In addition, EE is known to enhance BDNF production, raising the possibility that EE might be beneficial for MeCP2 KO phenotype. Indeed, recent data show that MeCP2 KO mice have reduced levels of BDNF in the brain and that crossing MeCP2 KO with BDNF overexpressing mice prolongs their life span and causes a normalization of the altered morpho-functional features. To analyze the effects of EE on a murine model of RTT, we reared MeCP2 KO in large groups in cages containing toys and wheels from birth. We found that EE strongly ameliorated motor coordination as assessed with the rotarod test at all the ages analyzed (P30-P60 tested every 5 days). EE KO show values similar to those of wild types reared in standard conditions. A trend for a prolonged life span was also observed. Indeed the median life duration of EE MeCP2 KO is longer by 14 days than life span of KO reared in standard conditions (Mann-Whitney test p= 0.055) suggesting that MeCP2 KO phenotype can be attenuated by environmental stimulation. Next, we investigated whether normal MeCP2 function is important for structure and plasticity of synaptic connections. Our electron-microscopic analysis revealed region-specific changes of both size and density of excitatory synapses in the hippocampus, cerebellum and S1 cortex of symptomatic MeCP2 KO mice. In contrast, inhibitory synapses showed a normal ultrastructural organization. Intriguingly, behavioural ameliorations shown by enriched MeCP2 KO mice are paralleled by anatomical changes in the brain. We found that EE induces an increase of excitatory synapse density both in the cerebellum and the S1 cortex (p < 0.05) indicating that structural neuronal plasticity is retained in the absence of MeCP2. Thus, this study suggest that it is possible to improve motor performances of MeCP2 KO mice with a behavioural-based therapy and that activity-dependent modifications of synaptic connections may underlie this process.
Environmental enrichment produces behavioural improvement, prolonged life span and structural synaptic plasticity in a mouse model of Rett’s syndrome
BOGGIO, ELENA MARIA;MORANDO, Laura;SASSOE' POGNETTO, Marco;GIUSTETTO, Maurizio
2007-01-01
Abstract
Mutations in the X-linked methyl-CpG binding protein 2 (Mecp2) gene cause the majority of Rett syndrome (RTT) cases, a neurological disorder that affects 1:10000-15000 girls worldwide. MeCP2 mouse mutants recapitulate many features found in human RTT. MeCP2 KO are characterized by a short life span, breathing defects, motor impairments, defects in basal synaptic transmission and plasticity and in neuronal formation. Hence, an accurate analysis of the mouse models represents an essential step towards the comprehension of the cause of RTT and is necessary for developing new therapies. Environmental enrichment (EE) is a housing conditions that facilitate enhanced sensory, cognitive, social and motor stimulation. In addition, EE is known to enhance BDNF production, raising the possibility that EE might be beneficial for MeCP2 KO phenotype. Indeed, recent data show that MeCP2 KO mice have reduced levels of BDNF in the brain and that crossing MeCP2 KO with BDNF overexpressing mice prolongs their life span and causes a normalization of the altered morpho-functional features. To analyze the effects of EE on a murine model of RTT, we reared MeCP2 KO in large groups in cages containing toys and wheels from birth. We found that EE strongly ameliorated motor coordination as assessed with the rotarod test at all the ages analyzed (P30-P60 tested every 5 days). EE KO show values similar to those of wild types reared in standard conditions. A trend for a prolonged life span was also observed. Indeed the median life duration of EE MeCP2 KO is longer by 14 days than life span of KO reared in standard conditions (Mann-Whitney test p= 0.055) suggesting that MeCP2 KO phenotype can be attenuated by environmental stimulation. Next, we investigated whether normal MeCP2 function is important for structure and plasticity of synaptic connections. Our electron-microscopic analysis revealed region-specific changes of both size and density of excitatory synapses in the hippocampus, cerebellum and S1 cortex of symptomatic MeCP2 KO mice. In contrast, inhibitory synapses showed a normal ultrastructural organization. Intriguingly, behavioural ameliorations shown by enriched MeCP2 KO mice are paralleled by anatomical changes in the brain. We found that EE induces an increase of excitatory synapse density both in the cerebellum and the S1 cortex (p < 0.05) indicating that structural neuronal plasticity is retained in the absence of MeCP2. Thus, this study suggest that it is possible to improve motor performances of MeCP2 KO mice with a behavioural-based therapy and that activity-dependent modifications of synaptic connections may underlie this process.
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
