Abstract
Rett syndrome is a severe pediatric neurological disorder caused by loss of function mutations within the gene encoding methyl CpG-binding protein 2 (MeCP2). Although MeCP2 is expressed near ubiquitously, the primary pathophysiology of Rett syndrome stems from impairments of nervous system function. One alteration within different regions of the MeCP2-deficient brain is the presence of hyper-excitable network responses. In the hippocampus, such responses exist despite there being an overall decrease in spontaneous excitatory drive within the network. In this study, we generated and used mathematical, neuronal network models to resolve this apparent paradox. We did this by taking advantage of previous mathematical modelling insights that indicated that decreased excitatory fluctuations, but not mean excitatory drive, more critically explain observed changes in hippocampal network oscillations from MeCP2-null mouse slices. Importantly, reduced excitatory fluctuations could also bring about hyper-excitable responses in our network models. Therefore, these results indicate that diminished excitatory fluctuations may be responsible for the hyper-excitable state of MeCP2-deficient hippocampal circuitry.
Highlights
Rett syndrome is an X-linked genetic disorder that largely affects females, and stems from mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2) [1]
Building on mechanistic understandings from our previous work [22], we showed in the previous section that reduced excitatory fluctuations could explain the changed characteristics of hippocampal SPAs produced in MeCP2-null slices relative to wildtype
Three principle observations emerge from our work: 1) changes in mean excitatory drive within the hippocampal network are not necessarily a critical component of these network alterations, 2) decreased excitatory fluctuations can be a critical factor in changes in hippocampal network oscillations in Rett syndrome, and 3) these fluctuations in excitatory levels can explain hyper-excitable responses in MeCP2-deficient hippocampal networks
Summary
Rett syndrome is an X-linked genetic disorder that largely affects females, and stems from mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2) [1]. While the severity of symptoms differs between individuals [2,3,4], common impairments in Rett syndrome patients include loss of fine motor skills, failure to develop speech, impaired locomotive ability, breathing irregularities, diminished cognitive ability, and seizures [2,5,6]. MeCP2 is near ubiquitously expressed, the CNS is more affected than peripheral tissues as a consequence of impaired MeCP2 function. Electroencephalography (EEG) studies conducted on Rett syndrome patients illustrate altered neural function. Diminished brain rhythmic activity, slower evoked sensory responsiveness [7], and spontaneous epileptiform discharges are commonly observed [7,8,9]. The underlying mechanisms that cause these alterations in network activity remain largely unknown
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
