Elevated MeCP2 in Mice Causes Neurodegeneration Involving Tau Dysregulation and Excitotoxicity: Implications for the Understanding and Treatment of MeCP2 Triplication Syndrome

• Published in: Molecular neurobiology 2018-12, Vol.55 (12), p.9057-9074
• Main Authors: Montgomery, Kristen R., Louis Sam Titus, A. S. C., Wang, Lulu, D’Mello, Santosh R.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Astrocytes; Astrocytes - drug effects; Astrocytes - metabolism; Ataxia; Biomedical and Life Sciences; Biomedicine; Brain - metabolism; Brain - pathology; Caspase 3 - metabolism; Cell Biology; Cerebellum; Cognitive ability; Cortex; Culture Media, Conditioned - pharmacology; Dizocilpine; Epilepsy; Excitotoxicity; Female; Gene Expression Regulation - drug effects; Glial fibrillary acidic protein; Granule cells; Hippocampus; Male; MeCP2 protein; Methyl-CpG binding protein; Methyl-CpG-Binding Protein 2 - metabolism; Mice; Mice, Transgenic; Models, Biological; Nerve Degeneration - genetics; Nerve Tissue Proteins - metabolism; Neurobiology; Neurodegeneration; Neurodegenerative diseases; Neurological diseases; Neurology; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Neurosciences; Neurotoxicity; Neurotoxins - toxicity; Patients; Purkinje cells; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Spinal Cord - metabolism; Syndrome; Tau protein; tau Proteins - metabolism; Transgenic mice; Up-Regulation - drug effects
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-018-1046-4

Expression of MeCP2 must be carefully regulated as a reduction or increase results in serious neurological disorders. We are studying transgenic mice in which the MeCP2 gene is expressed at about three times higher than the normal level. Male MeCP2-Tg mice, but not female mice, suffer motor and cognitive deficits and die at 18–20 weeks of age. MeCP2-Tg mice display elevated GFAP and Tau expression within the hippocampus and cortex followed by neuronal loss in these brain regions. Loss of Purkinje neurons, but not of granule neurons in the cerebellar cortex is also seen. Exposure of cultured cortical neurons to either conditioned medium from astrocytes (ACM) derived from male MeCP2-Tg mice or normal astrocytes in which MeCP2 is expressed at elevated levels promotes their death. Interestingly, ACM from male, but not female MeCP2-Tg mice, displays this neurotoxicity reflecting the gender selectivity of neurological symptoms in mice. Male ACM, but not female ACM, contains highly elevated levels of glutamate, and its neurotoxicity can be prevented by MK-801, indicating that it is caused by excitotoxicity. Based on the close phenotypic resemblance of MeCP2-Tg mice to patients with MECP2 triplication syndrome, we suggest for the first time that the human syndrome is a neurodegenerative disorder resulting from astrocyte dysfunction that leads to Tau-mediated excitotoxic neurodegeneration. Loss of cortical and hippocampal neurons may explain the mental retardation and epilepsy in patients, whereas ataxia likely results from the loss of Purkinje neurons.