Lovastatin fails to improve motor performance and survival in methyl-CpG-binding protein2-null mice
- Istituto di Ricerche Farmacologiche Mario Negri, Italy
Abstract
Previous studies provided evidence for the alteration of brain cholesterol homeostasis in 129.Mecp2-null mice, an experimental model of Rett syndrome. The efficacy of statins in improving motor symptoms and prolonging survival of mutant mice suggested a potential role of statins in the therapy of Rett syndrome. In the present study, we show that Mecp2 deletion had no effect on brain and serum cholesterol levels and lovastatin (1.5 mg/kg, twice weekly as in the previous study) had no effects on motor deficits and survival when Mecp2 deletion was expressed on a background strain (C57BL/6J; B6) differing from that used in the earlier study. These findings indicate that the effects of statins may be background specific and raise important issues to consider when contemplating clinical trials. The reduction of the brain cholesterol metabolite 24S-hydroxycholesterol found in B6.Mecp2-null mice suggests the occurrence of changes in brain cholesterol metabolism and the potential utility of using plasma levels of 24S-OHC as a biomarker of brain cholesterol homeostasis in RTT.
Article and author information
Author details
Roberto William Invernizzi
Funding
Istituto di Ricerche Farmacologiche Mario Negri (Intramural funding)
- Roberto William Invernizzi
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: The Istituto di Ricerche Farmacologiche "Mario Negri" adheres to the principle set out in the following law, regulations, and policies governing the care and use of laboratory animals: Italian Governing Law (D.lgs.26/2014; Authorisation n. 19/2008-A issued March 6, 2008 by Ministry of Health); Mario Negri Institutional Regulations and Policies providing internal authorization for persons conducting animal experiments (Quality Management System Certificate - UNI EN ISO 9001:2008 - Reg. N{degree sign} 6121); the NIH Guide for the Care and Use of Laboratory Animals (2011 edition) and EU directives and guidelines (EEC Council Directive 2010/63/UE). The statement of Compliance (Assurance) with the Public Health Service (PHS) Policy on Human Care and Use of Laboratory Animals has been recently reviewed (9/9/2014) and will expire on September 30, 2019 (Animal Welfare Assurance #A5023-01). The protocol was approved by the Italian Ministry of Health (Permit Number 946/2015-PR).
Copyright
© 2016, Villani et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Lovastatin fails to improve motor performance and survival in methyl-CpG-binding protein2-null mice
eLife 5:e22409.
https://doi.org/10.7554/eLife.22409
Further reading
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- Neuroscience
The relation between neural activity and behaviorally relevant variables is at the heart of neuroscience research. When strong, this relation is termed a neural representation. There is increasing evidence, however, for partial dissociations between activity in an area and relevant external variables. While many explanations have been proposed, a theoretical framework for the relationship between external and internal variables is lacking. Here, we utilize recurrent neural networks (RNNs) to explore the question of when and how neural dynamics and the network’s output are related from a geometrical point of view. We find that training RNNs can lead to two dynamical regimes: dynamics can either be aligned with the directions that generate output variables, or oblique to them. We show that the choice of readout weight magnitude before training can serve as a control knob between the regimes, similar to recent findings in feedforward networks. These regimes are functionally distinct. Oblique networks are more heterogeneous and suppress noise in their output directions. They are furthermore more robust to perturbations along the output directions. Crucially, the oblique regime is specific to recurrent (but not feedforward) networks, arising from dynamical stability considerations. Finally, we show that tendencies toward the aligned or the oblique regime can be dissociated in neural recordings. Altogether, our results open a new perspective for interpreting neural activity by relating network dynamics and their output.
