能提供下列三项之一的即可得分
1.电子书《Principle of Neural Science》 (Kandel et al., 2000)
2.电子版杂志《Neuron》2006年度
3.英文原版电子书《灵魂机器的时代》（雷·库兹维尔 著）注：是要英文原版的！
因为有版权保护措施，所以可能难找一些
拜托大家了，有追加分
參考答案:neuron
这可是<neuron>官方主页啊
有pdf格式的
列举一个链接
还有
Summary
Mutations or duplications in MECP2 cause Rett and Rett-like syndromes, neurodevelopmental disorders characterized by mental retardation, motor dysfunction, and autistic behaviors. MeCP2 is expressed in many mammalian tissues and functions as a global repressor of transcription; however, the molecular mechanisms by which MeCP2 dysfunction leads to the neural-specific phenotypes of RTT remain poorly understood. Here, we show that neuronal activity and subsequent calcium influx trigger the de novo phosphorylation of MeCP2 at serine 421 (S421) by a CaMKII-dependent mechanism. MeCP2 S421 phosphorylation is induced selectively in the brain in response to physiological stimuli. Significantly, we find that S421 phosphorylation controls the ability of MeCP2 to regulate dendritic patterning, spine morphogenesis, and the activity-dependent induction of Bdnf transcription. These findings suggest that, by triggering MeCP2 phosphorylation, neuronal activity regulates a program of gene expression that mediates nervous system maturation and that disruption of this process in individuals with mutations in MeCP2 may underlie the neural-specific pathology of RTT.
Introduction
Rett Syndrome (RTT) is an X-linked neurological disorder and a leading cause of mental retardation in females. Classical RTT is characterized by relatively normal development through the first 6–18 months of life, followed by an abrupt neurodevelopmental regression and stagnation that may result in loss of acquired skills such as purposeful movement and speech, deceleration of head growth, irregular breathing, stereotypical hand wringing, and the emergence of autistic behaviors (Hagberg et al., 1983; Moretti et al., 2006; Rett, 1966). The symptoms of RTT appear during early childhood when sensory experience is driving the synaptic reorganization required for the emergence of appropriately functioning circuits in the mature brain. This observation raised the hypothesis that the underlying cause of RTT is inappropriate synaptic connectivity or plasticity, possibly resulting from abnormal experience-dependent synaptic maturation, refinement, and/or maintenance (Zoghbi, 2003).
The majority of RTT cases are caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene (Amir et al., 1999). MeCP2 is a member of the family of methyl-CpG-binding domain (MBD) proteins that function as long-range transcriptional repressors that mediate developmental silencing through binding to methylated DNA (Klose et al., 2006; Lewis et al., 1992). In addition to its amino-terminal MBD, MeCP2 contains a transcriptional-repressor domain (TRD) and a C terminus that facilitates binding to methylated DNA (Chandler et al., 1999; Kriaucionis et al., 2003). The mutations found in RTT span the entire MeCP2 protein and include missense, nonsense, insertion, deletion, and splice-site variations (Bienvenu et al., 2006; Kriaucionis et al., 2003). Recently, reports of duplications of the entire MECP2 locus in some individuals with a RTT-like phenotype suggest that overexpression of MeCP2 also leads to Rett Syndrome (Ariani et al., 2004; Lugtenberg et al., 2006; Meins et al., 2005; Van Esch et al., 2005).
Like other MBD family proteins, MeCP2 is expressed in many somatic tissues. How disruption of this ubiquitously expressed protein leads to a predominantly neurological phenotype remains a central unresolved issue in the RTT field. One hint may lie in the fact that MeCP2 protein levels increase as neurons mature (Zoghbi, 2003). The high level of MeCP2 protein in mature neurons is consistent with a possible role for MeCP2 in synaptic processes.
Knockout mouse models with disrupted MeCP2 function mimic many key clinical features of RTT, including normal early postnatal life followed by developmental regression that results in motor impairment, irregular breathing, hindlimb clasping, and early mortality (Chen et al., 2001; Guy et al., 2001; Shahbazian et al., 2002). In addition, transgenic mice overexpressing wild-type MeCP2 protein also develop a RTT-like phenotype, suggesting that a precise level of MeCP2 expression is critical for proper brain development (Collins et al., 2004; Luikenhuis et al., 2004). Importantly, the conditional deletion of Mecp2 in postmitotic neurons recapitulates many of the phenotypes seen in the Mecp2 total null mouse (Chen et al., 2001; Guy et al., 2001), indicating that RTT is due to a specific defect in MeCP2 function in mature neurons.
Further supporting a role for MeCP2 in mature synaptic function and plasticity, Mecp2 null mice exhibit abnormalities in dendritic arborization (Chen et al., 2001; Kishi et al., 2004), basal synaptic transmission (Moretti et al., 2006), presynaptic function (Asaka et al., 2006; Moretti et al., 2006; Nelson et al., 2006), excitatory synaptic plasticity (Asaka et al., 2006; Moretti et al., 2006), and hippocampal and amygdalar learning (Moretti et al., 2006; Pelka et al., 2006). In addition, Mecp2 mutant mice exhibit reduced spontaneous cortical activity due to an imbalance between excitatory and inhibitory circuitry in the cortex (Dani et al., 2005). Notably, many of the phenotypes observed in RTT individuals and Mecp2 mutant mice—defects in dendritic branching, spine density, synaptic plasticity, learning and memory, and the maturation of inhibitory circuits—involve processes known to be influenced by experience-dependent neuronal activity (Katz et al., 1996). However, the molecular mechanisms by which MeCP2 dysfunction leads to these physiological and cellular defects and the relationship between MeCP2 and experience-dependent synaptic development remain undefined.
We recently found that membrane depolarization of neurons leads to phosphorylation of MeCP2, which correlates with the transcriptional induction of an activity-regulated gene, Bdnf (Chen et al., 2003). These findings, together with those of other groups (Ballas et al., 2005; Martinowich et al., 2003), suggested that dynamic regulation of MeCP2 by calcium influx may play a pivotal role in regulating specific programs of activity-dependent gene transcription that are important for nervous system function. In the present study, we investigated the significance of the calcium-dependent phosphorylation of MeCP2 for nervous system maturation and RTT. We find that phosphorylation of MeCP2 at a specific amino acid residue, S421, occurs selectively in the nervous system in response to neuronal activity. Mutation of MeCP2 at S421 blocks the ability of MeCP2 to restrict dendritic growth, spine maturation, and activate calcium-dependent Bdnf transcription in an in vitro overexpression model of RTT. These findings suggest that, by triggering MeCP2 phosphorylation, neuronal activity regulates a program of gene expression that mediates neuronal connectivity in the nervous system. The disruption of this process in individuals with mutations in MeCP2 may underlie the neural-specific pathology of RTT.
Results
Identification of S421 as a Site Required for Membrane Depolarization-Induced Phosphorylation of MeCP2
We have previously shown that membrane depolarization of neurons by exposure to elevated levels of extracellular potassium leads to the production of a slow-migrating species of MeCP2 as detected on a denaturing SDS-polyacrylamide gel (SDS-PAGE; Figure 1A, left). This slow-migrating form of MeCP2 disappears when extracts from membrane-depolarized neurons are treated with alkaline phosphatase (Figure 1A, right), suggesting that phosphorylation of MeCP2 may slow its migration on an SDS-PAGE gel. The slow-migrating form of MeCP2 exhibits reduced binding to methylated DNA, and its presence correlates with the induction of Bdnf promoter IV transcription in cortical cultures (see Figure 5 legend for Bdnf promoter nomenclature), raising the possibility that the phosphorylation of MeCP2 may inactivate the repressor function of MeCP2 (Chen et al., 2003). However, it remained to be determined whether phosphorylation, or another modification, regulates MeCP2 function in membrane-depolarized neurons and whether these modifications are relevant to the etiology of RTT
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