Sustained correction of associative learning deficits after brief, early treatment in a rat model of Fragile X Syndrome.

Autor:	Asiminas A; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH8 9XD, UK.; Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh EH8 9XD, UK.; Patrick Wild Centre, University of Edinburgh, Edinburgh EH8 9XD, UK., Jackson AD; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH8 9XD, UK.; Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh EH8 9XD, UK.; Patrick Wild Centre, University of Edinburgh, Edinburgh EH8 9XD, UK.; Centre for Brain Development and Repair, InStem, Bangalore 560065, India., Louros SR; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH8 9XD, UK.; Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh EH8 9XD, UK.; Patrick Wild Centre, University of Edinburgh, Edinburgh EH8 9XD, UK., Till SM; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH8 9XD, UK.; Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh EH8 9XD, UK.; Patrick Wild Centre, University of Edinburgh, Edinburgh EH8 9XD, UK., Spano T; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH8 9XD, UK.; Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh EH8 9XD, UK.; Patrick Wild Centre, University of Edinburgh, Edinburgh EH8 9XD, UK.; Centre for Brain Development and Repair, InStem, Bangalore 560065, India., Dando O; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH8 9XD, UK.; Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh EH8 9XD, UK.; Patrick Wild Centre, University of Edinburgh, Edinburgh EH8 9XD, UK.; UK Dementia Research Institute at the Edinburgh Medical School, University of Edinburgh, Edinburgh EH8 9XD, UK., Bear MF; Department of Brain and Cognitive Sciences, Howard Hughes Medical Institute, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Chattarji S; Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh EH8 9XD, UK.; Patrick Wild Centre, University of Edinburgh, Edinburgh EH8 9XD, UK.; Centre for Brain Development and Repair, InStem, Bangalore 560065, India., Hardingham GE; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH8 9XD, UK.; Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh EH8 9XD, UK.; Patrick Wild Centre, University of Edinburgh, Edinburgh EH8 9XD, UK.; UK Dementia Research Institute at the Edinburgh Medical School, University of Edinburgh, Edinburgh EH8 9XD, UK., Osterweil EK; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH8 9XD, UK.; Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh EH8 9XD, UK.; Patrick Wild Centre, University of Edinburgh, Edinburgh EH8 9XD, UK., Wyllie DJA; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH8 9XD, UK.; Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh EH8 9XD, UK.; Patrick Wild Centre, University of Edinburgh, Edinburgh EH8 9XD, UK.; Centre for Brain Development and Repair, InStem, Bangalore 560065, India., Wood ER; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH8 9XD, UK. p.kind@ed.ac.uk emma.wood@ed.ac.uk.; Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh EH8 9XD, UK.; Patrick Wild Centre, University of Edinburgh, Edinburgh EH8 9XD, UK.; Centre for Brain Development and Repair, InStem, Bangalore 560065, India., Kind PC; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH8 9XD, UK. p.kind@ed.ac.uk emma.wood@ed.ac.uk.; Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh EH8 9XD, UK.; Patrick Wild Centre, University of Edinburgh, Edinburgh EH8 9XD, UK.; Centre for Brain Development and Repair, InStem, Bangalore 560065, India.
Jazyk:	angličtina
Zdroj:	Science translational medicine [Sci Transl Med] 2019 May 29; Vol. 11 (494).
DOI:	10.1126/scitranslmed.aao0498
Abstrakt:	Fragile X Syndrome (FXS) is one of the most common monogenic forms of autism and intellectual disability. Preclinical studies in animal models have highlighted the potential of pharmaceutical intervention strategies for alleviating the symptoms of FXS. However, whether treatment strategies can be tailored to developmental time windows that define the emergence of particular phenotypes is unknown. Similarly, whether a brief, early intervention can have long-lasting beneficial effects, even after treatment cessation, is also unknown. To address these questions, we first examined the developmental profile for the acquisition of associative learning in a rat model of FXS. Associative memory was tested using a range of behavioral paradigms that rely on an animal's innate tendency to explore novelty. Fmr1 knockout (KO) rats showed a developmental delay in their acquisition of object-place recognition and did not demonstrate object-place-context recognition paradigm at any age tested (up to 23 weeks of age). Treatment of Fmr1 KO rats with lovastatin between 5 and 9 weeks of age, during the normal developmental period that this associative memory capability is established, prevents the emergence of deficits but has no effect in wild-type animals. Moreover, we observe no regression of cognitive performance in the FXS rats over several months after treatment. This restoration of the normal developmental trajectory of cognitive function is associated with the sustained rescue of both synaptic plasticity and altered protein synthesis. The findings provide proof of concept that the impaired emergence of the cognitive repertoire in neurodevelopmental disorders may be prevented by brief, early pharmacological intervention. (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze:	MEDLINE
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