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The phenotypic features of RTT include non-purposeful, stereotyped movements of hands, impaired mobility, intellectual disability, seizures, altered bone growth and premature osteoporosis and altered respiration. Unlike in autism, where brain size is increased, brain volume is reduced significantly in girls with RTT. Based on this, we hypothesized that RTT was a synaptic disorder, and given that glutamate is the most prevalent neurotransmitter in the brain, decided to characterize the expression of different types of glutamate receptors in post mortem samples of the prefrontal cortex from girls with RTT. We discovered that levels of glutamate receptors were higher in the cortex of girls with RTT, but only NMDA receptors were significantly overexpressed in young girls with RTT. This elevation occurs at the same time that glutamate levels are higher, indicating that homeostatic mechanisms regulating receptor expression have gone awry. These findings were the bases for clinical trials at KKI/Johns Hopkins investigating the efficacy of dextromethorphan, a NMDA receptor antagonist, for treatment of young girls with RTT.
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Journal of Neurochemistry (2023)
Maria Grazia Clemente, Dario Argiolas,Mary E Blue, Lino Argiolas,Angela Bitti,Laura Saderi,Andrea Piana,Giovanni Sotgiu,Roberto Antonucci
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