Methyl-CpG binding protein 2 (MeCP2) is a chromatin regulator highly expressed in mature neurons. Mutations of MECP2 gene cause Ͼ90% cases of Rett syndrome, a neurodevelopmental disorder featured by striking psychomotor dysfunction. In Mecp2-null mice, the motor deficits are associated with reduction of dopamine content in the striatum, the input nucleus of basal ganglia mostly composed of GABAergic neurons. Here we investigated the causal role of MeCP2 in modulation of striatal dopamine content and psychomotor function. We found that mice with selective removal of MeCP2 in forebrain GABAergic neurons, predominantly in the striatum, phenocopied Mecp2-null mice in dopamine deregulation and motor dysfunction. Selective expression of MeCP2 in the striatum preserved dopamine content and psychomotor function in both males and females. Notably, the dopamine deregulation was primarily confined to the rostral striatum, and focal deletion or reactivation of MeCP2 expression in the rostral striatum through adeno-associated virus effectively disrupted or restored dopamine content and locomotor activity, respectively. Together, these findings demonstrate that striatal MeCP2 maintains local dopamine content in a non-cell autonomous manner in the rostral striatum and that is critical for psychomotor control. Key words: dopamine; methyl-CpG binding protein 2; motor control; Rett syndrome; striatum IntroductionRett Syndrome (RTT) is a neurodevelopmental disorder primarily affecting females. Numerous RTT patients develop stereotypical hand wringing with ambulatory difficulties; these motor symptoms usually exacerbate with age and resemble Parkinson's symptoms later in life (Chahrour and Zoghbi, 2007; Temudo et al., 2008). More than 90% of RTT cases are caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2; Amir et al., 1999). The MeCP2 protein is highly expressed in mature neurons and is involved in regulating target gene transcription (Chahrour and Zoghbi, 2007;Guy et al., 2011). Loss of MeCP2 in mice mimics many RTT-like symptoms including late onset hypoactivity and deficits in motor coordination and motor skill learning (Chen et al., 2001;Guy et al., 2001;Shahbazian et al., 2002; Goffin et al., 2012;Kao et al., 2015). These motor phenotypes have been previously linked to reduced dopamine synthesis in the midbrain dopaminergic neurons (Samaco et al., 2009;Gantz et al., 2011; Panayotis et al., 2011). However, MeCP2 deficiency in aminergic neurons does not show motor learning impairments (Samaco et al., 2009), and selective expression of MeCP2 in catecholamine neurons of Mecp2-deficient mice partially ameliorate the RTT-like motor deficits , raising the possibility that MeCP2 in noncatecholamine neurons also plays a role in psychomotor control.We previously found that Mecp2-null mice show psychomotor deficits associated with aberrant molecular and cellular phenotypes in the striatum (Kao et al., 2015). The striatum is the input nucleus of the basal ganglia that resides in the forebrain and contr...
Rett Syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene. Affected individuals develop motor deficits including stereotypic hand movements, impaired motor learning and difficulties with movement. To understand the neural mechanisms of motor deficits in RTT, we characterized the molecular and cellular phenotypes in the striatum, the major input nucleus of the basal ganglia that controls psychomotor function, in mice carrying a null allele of Mecp2. These mice showed significant hypoactivity associated with impaired motor coordination and motor skill learning. We found that dopamine content was significantly reduced in the striatum of Mecp2 null mice. Reduced dopamine was accompanied by down-regulation of tyrosine hydroxylase and up-regulation of dopamine D2 receptors, particularly in the rostral striatum. We also observed that loss of MeCP2 induced compartment-specific alterations in the striatum, including reduced expression of μ-opioid receptors in the striosomes and increased number of calbindin-positive neurons in the striatal matrix. The total number of parvalbumin-positive interneurons and their dendritic arborization were also significantly increased in the striatum of Mecp2 null mice. Together, our findings support that MeCP2 regulates a unique set of genes critical for modulating motor output of the striatum, and that aberrant structure and function of the striatum due to MeCP2 deficiency may underlie the motor deficits in RTT.
Dry eye disease (DED) is a multifactorial illness with an increasingly high global prevalence and multiple risk factors that widely influences patients’ daily lives. It is essential to identify treatments with few or no side effects for patients with DED. We have reviewed studies published from 2001 to 2020 that investigated traditional Chinese medicine (TCM) and integrated Chinese and Western medicine for DED treatment. Current Chinese medicines used in DED therapy were categorized into four types, namely anti-oxidants, anti-inflammatory agents, hormone-like agents, and cell-repairing agents. Compound herbs, including Chi-Ju-Di-Huang-Wan and Qiming granule, can effectively alleviate dry eye symptoms. Moreover, patients with DED who were treated with Western medicine combined with TCM experienced significantly magnified therapeutic effects and reasonable costs of treatment. In conclusion, TCM can be a promising approach for treating DED, and combined treatment with TCM and Western drugs may represent a new strategy for improving the curative effect.
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