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Testing the excitation/inhibition imbalance hypothesis in a mouse model of the autism spectrum disorder: in vivo neurospectroscopy and molecular evidence for regional phenotypes

Gonçalves, Joana, Violante, Inês R., Sereno, José, Leitão, Ricardo A., Cai, Ying, Abrunhosa, Antero, Silva, Ana Paula, Silva, Alcino J. and Castelo-Branco, Miguel (2017) Testing the excitation/inhibition imbalance hypothesis in a mouse model of the autism spectrum disorder: in vivo neurospectroscopy and molecular evidence for regional phenotypes Molecular Autism, 8 (47). pp. 1-8.

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Abstract

Background

Excitation/inhibition (E/I) imbalance remains a widely discussed hypothesis in autism spectrum disorders (ASD). The presence of such an imbalance may potentially define a therapeutic target for the treatment of cognitive disabilities related to this pathology. Consequently, the study of monogenic disorders related to autism, such as neurofibromatosis type 1 (NF1), represents a promising approach to isolate mechanisms underlying ASD-related cognitive disabilities. However, the NF1 mouse model showed increased γ-aminobutyric acid (GABA) neurotransmission, whereas the human disease showed reduced cortical GABA levels. It is therefore important to clarify whether the E/I imbalance hypothesis holds true. We hypothesize that E/I may depend on distinct pre- and postsynaptic push-pull mechanisms that might be are region-dependent.

Methods

In current study, we assessed two critical components of E/I regulation: the concentration of neurotransmitters and levels of GABA(A) receptors. Measurements were performed across the hippocampi, striatum, and prefrontal cortices by combined in vivo magnetic resonance spectroscopy (MRS) and molecular approaches in this ASD-related animal model, the Nf1 +/− mouse.

Results

Cortical and striatal GABA/glutamate ratios were increased. At the postsynaptic level, very high receptor GABA(A) receptor expression was found in hippocampus, disproportionately to the small reduction in GABA levels. Gabaergic tone (either by receptor levels change or GABA/glutamate ratios) seemed therefore to be enhanced in all regions, although by a different mechanism.

Conclusions

Our data provides support for the hypothesis of E/I imbalance in NF1 while showing that pre- and postsynaptic changes are region-specific. All these findings are consistent with our previous physiological evidence of increased inhibitory tone. Such heterogeneity suggests that therapeutic approaches to address neurochemical imbalance in ASD may need to focus on targets where convergent physiological mechanisms can be found.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Psychology
Authors :
NameEmailORCID
Gonçalves, Joana
Violante, Inês R.ines.violante@surrey.ac.uk
Sereno, José
Leitão, Ricardo A.
Cai, Ying
Abrunhosa, Antero
Silva, Ana Paula
Silva, Alcino J.
Castelo-Branco, Miguel
Date : 19 September 2017
Identification Number : 10.1186/s13229-017-0166-4
Copyright Disclaimer : © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Uncontrolled Keywords : Autism spectrum disorders; Neurofibromatosis type 1; Excitation/inhibition imbalance; GABA(A) receptor; Magnetic resonance spectroscopy
Depositing User : Clive Harris
Date Deposited : 12 Apr 2018 07:33
Last Modified : 12 Apr 2018 07:33
URI: http://epubs.surrey.ac.uk/id/eprint/846189

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