RESUMO
Environmental factors such as nutrition and housing can influence behavioral and anatomical characteristics of several neurological disorders, including Rett syndrome (RTT). RTT is associated with mutations in the X-linked gene encoding MeCP2, a transcriptional repressor that binds methylated DNA. While direct genetic intervention in humans is impossible at this time, motor and cognitive deficits in RTT may be ameliorated through manipulations of epigenetic/environmental factors. For example, studies in rodents suggest that choline nutrient supplementation during critical periods of brain development enhances cholinergic neurotransmission, alters neuronal size and distribution, and facilitates performance of memory and motoric tasks. Recent work in a mouse model of RTT shows that enhancing maternal nutrition through choline supplementation improves both anatomical and behavioral symptoms in the mutant offspring. We describe here cellular and molecular mechanisms that may underlie this specific enhancement and may provide more general insights into mechanisms underlying gene-environment interactions in neurological disorders.
Assuntos
Modelos Animais de Doenças , Fenômenos Fisiológicos da Nutrição/fisiologia , Síndrome de Rett , Acetilcolina/metabolismo , Animais , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Colina/metabolismo , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/fisiologia , Genes Ligados ao Cromossomo X , Humanos , Proteína 2 de Ligação a Metil-CpG/genética , Camundongos , Mutação , Neurônios/patologia , Síndrome de Rett/dietoterapia , Síndrome de Rett/genética , Síndrome de Rett/metabolismo , Transdução de Sinais/genéticaRESUMO
Rett syndrome (RTT), the second leading cause of mental retardation in girls, is caused by mutations in the X-linked gene for methyl-CpG-binding protein 2 (MeCP2), a transcriptional repressor. In addition to well-documented neuroanatomical and behavioral deficits, RTT is characterized by reduced markers of cholinergic activity and general neuronal health. Previously, we have shown that early postnatal choline (Cho) supplementation improves behavioral and neuroanatomical symptoms in a mouse model of RTT (Mecp2(1lox) mice). In this study, we use NMR spectroscopy to quantify the relative amounts of Cho, Glutamate (Glu), Glutamine (Gln), and N-acetyl aspartate (NAA) in the brains of wild type and mutant mice at 21, 35, and 42 days of age and in mice receiving postnatal Cho supplementation. We find that the mutant mice have reduced levels of Cho, Glu, and NAA, but elevated Gln levels, compared with their wild type littermates. These differences emerge at different developmental ages. Cho supplementation increases NAA levels, a marker of neuronal integrity, but has no effect on Cho, Glu, or Gln. These data suggest that postnatal nutritional supplementation may improve neuronal function and could serve as a therapeutic agent for human RTT patients.
Assuntos
Encéfalo/efeitos dos fármacos , Colina/administração & dosagem , Suplementos Nutricionais , Nootrópicos/administração & dosagem , Síndrome de Rett/metabolismo , Fatores Etários , Animais , Animais Recém-Nascidos , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Colina/metabolismo , Creatina/metabolismo , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Ácido Glutâmico/metabolismo , Glutamina/metabolismo , Histona Desacetilases/genética , Espectroscopia de Ressonância Magnética/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Síndrome de Rett/dietoterapia , Síndrome de Rett/genética , Síndrome de Rett/patologia , Análise EspectralRESUMO
Rett syndrome (RTT) is an autistic spectrum developmental disorder associated with mutations in the X-linked Mecp2 gene, and severe behavioural and neuropathological deficits. In a mouse model of RTT (Mecp2(1lox)), we examined whether environmental enrichment (EE) alters behavioural performance and regional brain volume. At weaning, Mecp2(1lox) and control mice were assigned to enriched or standard housing. From postnatal day 29 to 43, mice were subjected to behavioural tasks measuring motor and cognitive performance. At postnatal day 44, volumes of whole brain, cerebellum, ventricles, and motor cortex were measured using magnetic resonance imaging. EE provided subtle improvements to locomotor activity and contextual fear conditioning in Mecp2(1lox) mice. Additionally, EE reduced ventricular volumes, which correlated with improved locomotor activity, suggesting that neuroanatomical changes contribute to improved behaviour. Our results suggest that post-weaning EE may provide a non-invasive palliative treatment for RTT.
Assuntos
Ventrículos Cerebrais/anatomia & histologia , Meio Ambiente , Proteína 2 de Ligação a Metil-CpG/genética , Atividade Motora/fisiologia , Síndrome de Rett/fisiopatologia , Análise de Variância , Animais , Cerebelo/anatomia & histologia , Cerebelo/fisiologia , Ventrículos Cerebrais/fisiologia , Cognição/fisiologia , Condicionamento Psicológico/fisiologia , Modelos Animais de Doenças , Medo/fisiologia , Medo/psicologia , Imageamento por Ressonância Magnética , Masculino , Memória/fisiologia , Proteína 2 de Ligação a Metil-CpG/deficiência , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Córtex Motor/anatomia & histologia , Córtex Motor/fisiologia , Mutação , Síndrome de Rett/genética , Síndrome de Rett/patologiaRESUMO
The expression mechanism of long-term potentiation (LTP) remains controversial. Here we combine electrophysiology and Ca(2+) imaging to examine the role of silent synapses in LTP expression. Induction of LTP fails to change p(r) at these synapses but instead mediates an unmasking process that is sensitive to the inhibition of postsynaptic membrane fusion. Once unmasked, however, further potentiation of formerly silent synapses leads to an increase in p(r). The state of the synapse thus determines how LTP is expressed.
