The GABAA Receptor as a Therapeutic Target for Neurodevelopmental Disorders

Braat, Sien; Kooy, R. Frank

doi:10.1016/j.neuron.2015.03.042

Cited by 257 publications

(227 citation statements)

References 137 publications

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“…In Rett syndrome, GABAergic neurons alone account for the majority of behavioral symptoms (Chao et al, 2010), with somatostatin- and parvalbumin-expressing interneurons each mediating non-overlapping Rett-like phenotypes (Ito-Ishida et al, 2015). Disrupted GABAergic signaling has been consistently demonstrated in neurodevelopmental disorders such as Rett syndrome, fragile X syndrome, MECP2 duplication syndrome, and Dravet syndrome (Braat and Kooy, 2015). By comparison, the involvement of the subcortical glutamatergic system has not been as thoroughly studied.…”

Section: Discussionmentioning

confidence: 99%

Molecular and Neural Functions of Rai1 , the Causal Gene for Smith-Magenis Syndrome

Huang

Guenthner

et al. 2016

Neuron

110

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SUMMARY Haploinsufficiency of Retinoic Acid Induced 1 (RAI1) causes Smith-Magenis syndrome (SMS), which is associated with diverse neurodevelopmental and behavioral symptoms as well as obesity. RAI1 encodes a nuclear protein but little is known about its molecular function or the cell types responsible for SMS symptoms. Using genetically engineered mice, we found that Rai1 preferentially occupies DNA regions near active promoters and promotes the expression of a group of genes involved in circuit assembly and neuronal communication. Behavioral analyses demonstrated that pan-neural loss of Rai1 causes deficits in motor function, learning, and food intake. These SMS-like phenotypes are produced by loss of Rai1 function in distinct neuronal types: Rai1 loss in inhibitory neurons or subcortical glutamatergic neurons causes learning deficits, while Rai1 loss in Sim1+ or SF1+ cells causes obesity. By integrating molecular and organismal analyses, our study suggests potential therapeutic avenues for a complex neurodevelopmental disorder.

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Section: Discussionmentioning

confidence: 99%

Molecular and Neural Functions of Rai1 , the Causal Gene for Smith-Magenis Syndrome

Huang

Guenthner

et al. 2016

Neuron

110

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“…These emotional-evaluative changes may clearly have downstream implications for cortisol release. Additionally, the gamma amino butyric acid neurotransmitter system appears to be commonly disordered in many neurodevelopmental disorders, including FXS (Braat & Kooy, 2015). Preclinically, FMRP has been shown to regulate GABA-ergic synaptic vesicle dynamics within the hippocampus of the Fmr1 KO mouse model, (Broek et al, 2016).…”

Section: Kind Regards Rebecca Hardiman and Alison Brattmentioning

confidence: 99%

Hypothalamic-pituitary-adrenal axis function in Fragile X Syndrome and its relationship to behaviour: A systematic review

Hardiman

Bratt

2016

Physiology & Behavior

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Fragile X Syndrome (FXS) is characterised by features including anxiety and autistic-like behaviour, which led to early hypotheses that aberrant physiological arousal may underlie the behavioural phenotype. In line with this, several lines of evidence suggest that the HypothalamicPituitary-Adrenal (HPA) axis may be altered in the syndrome. This review collates evidence to determine the nature of HPA axis baseline activity and reactivity (as measured by glucocorticoid levels) differences in FXS, and its relationship to behaviour. Through a search electronic databases, 15 papers were identified which provided data on humans with FXS or the FMR1 knockout mouse model. The findings across studies are mixed, though trends in the findings can be seen, including elevations in cortisol levels, particularly in males. Preliminary findings also highlight associations between cortisol levels and key behaviours associated with the syndrome, such as gaze avoidance. Areas for future research are discussed. Many thanks to the editor and to the reviewers for taking the time to kindly re-review the manuscript and provide useful feedback. I have addressed the issues raised and made amendments, as detailed individually below, using tracked changes:As requested, I have re-structured the article to align to the review questions. I have, however, addressed gender differences according to each aspect of the cortisol release (baseline activity, magnitude/ duration of response, for humans and animals) following the discussion on that specific topic, and clearly marked this with sub-headings. However, I hope that I have now better highlighted the themes in gender differences observed, and have included a separate table on this issue, as requested.When referring to each study in the text, I have briefly stated how many individuals were involved and what the ages of the individuals. I have done this for the studies with human participants, as from drafting this for the animal studies (which are addressed often is less detail in the text) this became very cumbersome to read. However, the animal results are presented directly alongside the sample sizes in Table 1, which I hope will make this interpretation more simple.On p15 we mention the findings of Roberts et al (2009) in relation to the magnitude of cortisol responses. The authors of this study split their analyses according to two groups: those individuals with FXS who met the criteria for autism, and those who did not. The reviewer requested that this discussion be moved to the section on cortisol and behaviour. Given the paucity of studies discussing the magnitude of cortisol responses in this group, I have proposed that we leave this study here (as there is no option to present the results without referring to the grouping according to autism symptomatology) but to note that a further discussion on the topic is included later in the manuscript. Please do let me know if this is acceptable.The first paragraph on page 17 was noted to be out of place. I have now clarified the int...

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“…Mutation and altered activity of NMDA receptors have been associated with autism and epilepsy (Burnashev & Szepetowski 2015) and with major depressive and bipolar disorders (Ghasemi et al 2014). The GABA A receptors (GABA A Rs) are heteropentameric ligand-gated chloride and bicarbonate channels that promote hyperpolarizing postsynaptic responses, that is, the inhibitory postsynaptic potential when activated (Braat & Kooy 2015, Farrant & Nusser 2005. The sigma-1 receptor is a 25 kDa protein that has been associated with the endoplasmic reticulum, R149 Review r a prough and others DHEA activation of receptors 56 3 :…”

Section: Dhea Action In Neuronal/cns Cellsmentioning

confidence: 99%

Novel mechanisms for DHEA action

Prough

Clark

Klinge

2016

Journal of Molecular Endocrinology

134

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Dehydroepiandrosterone (3β-hydroxy-5-androsten-17-one, DHEA), secreted by the adrenal cortex, gastrointestinal tract, gonads, and brain, and its sulfated metabolite DHEA-S are the most abundant endogeneous circulating steroid hormones. DHEA actions are classically associated with age-related changes in cardiovascular tissues, female fertility, metabolism, and neuronal/CNS functions. Early work on DHEA action focused on the metabolism to more potent sex hormones, testosterone and estradiol, and the subsequent effect on the activation of the androgen and estrogen steroid receptors. However, it is now clear that DHEA and DHEA-S act directly as ligands for many hepatic nuclear receptors and G-protein-coupled receptors. In addition, it can function to mediate acute cell signaling pathways. This review summarizes the molecular mechanisms by which DHEA acts in cells and animal models with a focus on the 'novel' and physiological modes of DHEA action.

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The GABAA Receptor as a Therapeutic Target for Neurodevelopmental Disorders

Cited by 257 publications

References 137 publications

Molecular and Neural Functions of Rai1 , the Causal Gene for Smith-Magenis Syndrome

Molecular and Neural Functions of Rai1 , the Causal Gene for Smith-Magenis Syndrome

Hypothalamic-pituitary-adrenal axis function in Fragile X Syndrome and its relationship to behaviour: A systematic review

Novel mechanisms for DHEA action

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