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Title: Testing the excitation/inhibition imbalance hypothesis in a mouse model of the autism spectrum disorder: in vivo neurospectroscopy and molecular evidence for regional phenotypes
Authors: Gonçalves, Joana 
Violante, Inês R. 
Sereno, José 
Leitão, Ricardo A. 
Cai, Ying
Abrunhosa, Antero 
Silva, Ana Paula 
Silva, Alcino J.
Castelo-Branco, Miguel 
Keywords: Autism spectrum disorders; Neurofibromatosis type 1; Excitation/inhibition imbalance; GABA(A) receptor; Magnetic resonance spectroscopy
Issue Date: 2017
Publisher: Springer Nature
Project: grants MEDPERSYST, POCI-01-0145-FEDER-016428, BIGDATIMAGE, CENTRO-01-0145-FEDER-000016 financed by Centro 2020 FEDER, COMPETE, FLAD Life Sciences Ed 2 2016, COMPETE, POCI-01-0145-FEDER- 007440, FCT. UID/NEU/04539/2013–2020 to MCB, as well as by MH084315 to AJS 
Serial title, monograph or event: Molecular Autism
Volume: 8
Issue: 1
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 ASDrelated 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.
ISSN: 2040-2392
DOI: 10.1186/s13229-017-0166-4
Rights: openAccess
Appears in Collections:I&D CNC - Artigos em Revistas Internacionais
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FMUC Medicina - Artigos em Revistas Internacionais

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