Positron Emission Tomography (PET) Quantification of GABAA Receptors in the Brain of Fragile X Patients

D’Hulst, Charlotte; Heulens, Inge; Aa, Nathalie Van der; Goffin, Karolien; Koole, Michel; Porke, Kathleen; Velde, Marc Van de; Rooms, Liesbeth; Paesschen, Wim Van; Esch, Hilde Van; Laere, Koen Van; Kooy, R. Frank

doi:10.1371/journal.pone.0131486

Cited by 48 publications

(29 citation statements)

References 31 publications

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“…Loss of the thalamic gamma oscillator, and weaker or less refined thalamocortical input are likely contributors to the loss of EGOs. Thalamus is the region with the largest reduction of GABA A receptor binding in FXS patients 43 . Fragile X granules are expressed in thalamocortical axons in mouse (but not in thalamic interneurons or reticular neurons) 44 and glutamatergic synaptic development at thalamocortical synapses is delayed in FMR-KO mice 45 .…”

Section: Discussionmentioning

confidence: 99%

Sensory hypo-excitability in a rat model of fetal development in Fragile X Syndrome

Berzhanskaya

Phillips

Shen

et al. 2016

Sci Rep

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Fragile X syndrome (FXS) is characterized by sensory hyper-sensitivity, and animal models suggest that neuronal hyper-excitability contributes to this phenotype. To understand how sensory dysfunction develops in FXS, we used the rat model (FMR-KO) to quantify the maturation of cortical visual responses from the onset of responsiveness prior to eye-opening, through age equivalents of human juveniles. Rather than hyper-excitability, visual responses before eye-opening had reduced spike rates and an absence of early gamma oscillations, a marker for normal thalamic function at this age. Despite early hypo-excitability, the developmental trajectory of visual responses in FMR-KO rats was normal, and showed the expected loss of visually evoked bursting at the same age as wild-type, two days before eye-opening. At later ages, during the third and fourth post-natal weeks, signs of mild hyper-excitability emerged. These included an increase in the visually-evoked firing of regular spiking, presumptive excitatory, neurons, and a reduced firing of fast-spiking, presumptive inhibitory, neurons. Our results show that early network changes in the FMR-KO rat arise at ages equivalent to fetal humans and have consequences for excitability that are opposite those found in adults. This suggests identification and treatment should begin early, and be tailored in an age-appropriate manner.

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Section: Discussionmentioning

confidence: 99%

Sensory hypo-excitability in a rat model of fetal development in Fragile X Syndrome

Berzhanskaya

Phillips

Shen

et al. 2016

Sci Rep

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“…In the Drosophila model, limited research available has demonstrated that a GABA A receptor reduction can lead to behavioral impairments. However, other research from FXS models indicated that the mechanism was likely more complicated and possibly indirect due to not only variable GABA metabolisms but also regional specificity [ 40 , 42 , 43 ]. For example, vision process is modulated by different GABA receptors in spread brain via tonic inhibition, such as temporal cortex, lateral geniculate nucleus (LGN) of the thalamus, and vision cortex [ 44 , 45 ], while tonic inhibition is mediated via extrasynaptic α 5- and δ -containing GABA A Rs [ 40 , 44 ].…”

Section: Decreased Expression Of Gaba Receptor Subunits In Fxs Modmentioning

confidence: 99%

Impaired GABA Neural Circuits Are Critical for Fragile X Syndrome

Gao

Yang

et al. 2018

Neural Plasticity

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Fragile X syndrome (FXS) is an inheritable neuropsychological disease caused by silence of the fmr1 gene and the deficiency of Fragile X mental retardation protein (FMRP). Patients present neuronal alterations that lead to severe intellectual disability and altered sleep rhythms. However, the neural circuit mechanisms underlying FXS remain unclear. Previous studies have suggested that metabolic glutamate and gamma-aminobutyric acid (GABA) receptors/circuits are two counter-balanced factors involved in FXS pathophysiology. More and more studies demonstrated that attenuated GABAergic circuits in the absence of FMRP are critical for abnormal progression of FXS. Here, we reviewed the changes of GABA neural circuits that were attributed to intellectual-deficient FXS, from several aspects including deregulated GABA metabolism, decreased expressions of GABA receptor subunits, and impaired GABAergic neural circuits. Furthermore, the activities of GABA neural circuits are modulated by circadian rhythm of FMRP metabolism and reviewed the abnormal condition of FXS mice or patients.

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“…First, we have taken a fixed value of glutamate−GABA concentration over the entire brain commensurate with measurements from MRS using single-voxel spectroscopy. However, the concentrations of these neurotransmitters are variable across different areas which can be measured from positron emission tomography (PET) recordings (D'Hulst et al, 2015). Nonetheless, a detailed analysis with glutamate−GABA values in individual brain areas contributing to resting-state dynamics remains out of the scope at this point due to lack of availability of detailed data but will be an interesting issue to resolve in future as wand when such data is available.…”

Section: Discussionmentioning

confidence: 99%

Multiscale dynamic mean field model to relate resting-state brain dynamics with local cortical excitatory-inhibitory neurotransmitter homeostasis in health and disease

Naskar¹,

Vattikonda²,

Deco

et al. 2018

Preprint

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Previous neuro-computational studies have established the connection of spontaneous resting-state brain activity with "large-scale" neuronal ensembles using dynamic mean field approach and showed the impact of local excitatory−inhibitory (E−I) balance in sculpting dynamical patterns.Here, we argue that whole brain models that link multiple scales of physiological organization namely brain metabolism that governs synaptic concentrations of gamma-aminobutyric acid (GABA) and glutamate on one hand and neural field dynamics that operate on the macroscopic scale. The multiscale dynamic mean field (MDMF) model captures the synaptic gating dynamics over a cortical macrocolumn as a function of neurotransmitter kinetics. Multiple MDMF units were placed in brain locations guided by an anatomical parcellation and connected by tractography data from diffusion tensor imaging. The resulting whole-brain model generates the resting-state functional connectivity and also reveal that optimal configurations of glutamate and GABA captures the dynamic working point of the brain, that is the state of maximum metsatability as observed in BOLD signals. To demonstrate test-retest reliability we validate the observation that healthy resting brain dynamics is governed by optimal glutamate-GABA configurations using two different brain parcellations for model set-up. Furthermore, graph theoretical measures of segregation (modularity and clustering coefficient) and integration (global efficiency and characteristic path length) on the functional connectivity generated from healthy and pathological brain network studies could be explained by the MDMF model. In conclusion, the MDMF model could relate the various scales of observations from neurotransmitter concentrations to dynamics of synaptic gating to whole-brain resting-state network topology in health and disease.Key words: GABA, Glutamate, metastability, resting-state functional connectivity, structural connectivity, network measures, epilepsy, and schizophrenia. and structured resting-state dynamics of brain. The problem is further compounded by the fact that brain parameters, such as the proportion of different neurons and neurotransmitter types (glutamate, gamma-aminobutyric acid (GABA), etc.) with their associated synaptic properties cannot be manipulated independently in living system to delineate their role in brain function (Prinz, 2008). Due to these in vivo practical constraints, physiologically realistic whole brain network models are favourable candidates to overcome and manipulate experimentally inaccessible parameter(s) of neuronal networks in brain. Following this line of reasoning, mean field approach, consisting of coupled stochastic differential equations could provide appropriate neuro-computational framework to study missing link between micro-scale state variables with whole-brain network dynamics (Breakspear et al., 2017). Moreover, the computational brain network modeling could be used to explore the underlying mechanisms of human brain functions, such as at the resti...

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Positron Emission Tomography (PET) Quantification of GABAA Receptors in the Brain of Fragile X Patients

Cited by 48 publications

References 31 publications

Sensory hypo-excitability in a rat model of fetal development in Fragile X Syndrome

Sensory hypo-excitability in a rat model of fetal development in Fragile X Syndrome

Impaired GABA Neural Circuits Are Critical for Fragile X Syndrome

Multiscale dynamic mean field model to relate resting-state brain dynamics with local cortical excitatory-inhibitory neurotransmitter homeostasis in health and disease

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