GABA deficiency in NF1

Violante, Inês R.; Patrício, Miguel; Bernardino, Inês; Rebola, José; Abrunhosa, Antero; Ferreira, Nuno C.

doi:10.1212/wnl.0000000000003044

Cited by 36 publications

(21 citation statements)

References 35 publications

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“…These results somewhat contradict those of Rodrigues et al (40), who found a preservation of NAA values but an increase in MyoInositol/Creatinine and Choline/Creatinine ratios in the basal ganglia with the use of a larger sample (42 NF1 subjects aged 4 to 24 years and 25 healthy controls) regardless of the UBOs status (presence or absence). Lastly, Violante et al (41) used magnetic resonance spectroscopy (MRS) and [11C]-flumazenil PET, to compare 14 NF1 adults and 13 matched controls. These authors found a lower gamma-aminobutyric acid (GABA) concentration in the visual cortex and the frontal eye fields (FEF) (11.5 and 22% respectively), and a reduction in the binding of GABA A receptors in the left parieto-occipital cortex, midbrain and thalami, which were not explained by a lower GM volume.…”

Section: Multimodal Approachmentioning

confidence: 99%

Can the Cognitive Phenotype in Neurofibromatosis Type 1 (NF1) Be Explained by Neuroimaging? A Review

et al. 2020

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Section: Multimodal Approachmentioning

confidence: 99%

Can the Cognitive Phenotype in Neurofibromatosis Type 1 (NF1) Be Explained by Neuroimaging? A Review

et al. 2020

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“…In humans, we have found that excitation/inhibition balance is altered in the visual and medial frontal cortex of patients with NF1, as a consequence of reduced GABA concentration [ 13 , 14 ]. More recently, we observed a decreased binding of GABA(A) receptors (GABA(A)R) in patients in the parieto-occipital cortex, midbrain, and thalamus suggesting neurodevelopmental synaptopathy both at the pre- and postsynaptic level [ 15 , 16 ]. However, levels of GABA and GABA(A)R have never been assessed in NF1 mutant mice, which is important to link the preclinical model to clinical observations and to the development of therapies targeting GABAergic pathways.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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BackgroundExcitation/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.MethodsIn 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.ResultsCortical 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.ConclusionsOur 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.

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“…Lastly, the link between GABA and hemodynamic response, as measured by the BOLD signal, is complex. GABA concentration has been shown to be reduced in patients with NF1 (47), and more research is warranted to determine how this may play a role in the BOLD response in patients with NF1 (48). …”

Section: Discussionmentioning

confidence: 99%

Risky Decision Making in Neurofibromatosis Type 1: An Exploratory Study

Jonas¹,

Roh²,

Montojo³

et al. 2017

Biological Psychiatry: Cognitive Neuroscience and Neuroimaging

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Background Neurofibromatosis type 1 (NF1) is a monogenic disorder affecting cognitive function. About one third of children with NF1 have attentional disorders, and the cognitive phenotype is characterized by impairment in prefrontally-mediated functions. Mouse models of NF1 show irregularities in GABA release and striatal dopamine metabolism. We hypothesized that youth with NF1 would show abnormal behavior and neural activity on a task of risk-taking reliant on prefrontal-striatal circuits. Methods Youth with NF1 (N=29) and demographically comparable healthy controls (N=22), ages 8-19, were administered a developmentally sensitive gambling task, in which they chose between low-risk gambles with a high probability of obtaining a small reward, and high-risk gambles with a low probability of obtaining a large reward. We used functional magnetic resonance imaging (fMRI) to investigate neural activity associated with risky decision making, as well as age-associated changes in these behavioral and neural processes. Results Behaviorally, youth with NF1 tended to make fewer risky decisions than controls. Neuroimaging analyses revealed significantly reduced neural activity across multiple brain regions involved in higher-order semantic processing and motivation (i.e., anterior cingulate, paracingulate, supramarginal, and angular gyri) in patients with NF1 relative to controls during the task. We also observed atypical age-associated changes in neural activity in patients with NF1, such that during risk taking, neural activity tended to decrease with age in controls, whereas it tended to increase with age in patients with NF1. Conclusions Findings suggest that developmental trajectories of neural activity during risky decision-making may be disrupted in youth with NF1.

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GABA deficiency in NF1

Cited by 36 publications

References 35 publications

Can the Cognitive Phenotype in Neurofibromatosis Type 1 (NF1) Be Explained by Neuroimaging? A Review

Can the Cognitive Phenotype in Neurofibromatosis Type 1 (NF1) Be Explained by Neuroimaging? A Review

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

Risky Decision Making in Neurofibromatosis Type 1: An Exploratory Study

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