A randomised controlled trial of bumetanide in the treatment of autism in children

Lemonnier, Éric; Degrez, Céline; Phelep, Morgane; Tyzio, Roman; Josse, Florent; Grandgeorge, Marine; Hadjikhani, Nouchine; Ben-Ari, Yehezkel

doi:10.1038/tp.2012.124

Cited by 255 publications

(242 citation statements)

References 85 publications

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“…Data are represented as mean ± SEM *P < 0.05, **P < 0.01, ***P < 0.001, determined by one-way ANOVA with Bonferroni correction. (42,43). NKCC1 also interacts with DISC1 to regulate the risk of schizophrenia (44).…”

Section: Discussionmentioning

confidence: 99%

KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome

Tang

Kim

Zhou

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

199

179

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Rett syndrome is a severe form of autism spectrum disorder, mainly caused by mutations of a single gene methyl CpG binding protein 2 (MeCP2) on the X chromosome. Patients with Rett syndrome exhibit a period of normal development followed by regression of brain function and the emergence of autistic behaviors. However, the mechanism behind the delayed onset of symptoms is largely unknown. Here we demonstrate that neuron-specific K+-Cl− cotransporter2 (KCC2) is a critical downstream gene target of MeCP2. We found that human neurons differentiated from induced pluripotent stem cells from patients with Rett syndrome showed a significant deficit in KCC2 expression and consequently a delayed GABA functional switch from excitation to inhibition. Interestingly, overexpression of KCC2 in MeCP2-deficient neurons rescued GABA functional deficits, suggesting an important role of KCC2 in Rett syndrome. We further identified that RE1-silencing transcriptional factor, REST, a neuronal gene repressor, mediates the MeCP2 regulation of KCC2. Because KCC2 is a slow onset molecule with expression level reaching maximum later in development, the functional deficit of KCC2 may offer an explanation for the delayed onset of Rett symptoms. Our studies suggest that restoring KCC2 function in Rett neurons may lead to a potential treatment for Rett syndrome.

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Section: Discussionmentioning

confidence: 99%

KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome

Tang

Kim

Zhou

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

199

179

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“…A disturbance in GABAergic function at this stage causes neurodevelopmental disorders, such as mental retardation, Angelman syndrome, epilepsy, and autism (21). Recently, bumetanide has been shown to improve behavior in children with autism by reducing GABAergic excitation (22). GABA also acts as an excitatory neurotransmitter in the mature but pathological brain (23).…”

Section: Discussionmentioning

confidence: 99%

Seasonal induction of GABAergic excitation in the central mammalian clock

Farajnia

Westering

Meijer

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

107

129

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The balance between excitation and inhibition is essential for the proper function of neuronal networks in the brain. The inhibitory neurotransmitter γ-aminobutyric acid (GABA) contributes to the network dynamics within the suprachiasmatic nucleus (SCN), which is involved in seasonal encoding. We investigated GABAergic activity and observed mainly inhibitory action in SCN neurons of mice exposed to a short-day photoperiod. Remarkably, the GABAergic activity in a long-day photoperiod shifts from inhibition toward excitation. The mechanistic basis for this appears to be a change in the equilibrium potential of GABA-evoked current. These results emphasize that environmental conditions can have substantial effects on the function of a key neurotransmitter in the central nervous system.S easonal changes in the photoperiod of the Earth's temperate zones affect the behavior and physiology of many organisms (1). The central circadian clock, located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus, can adapt to changes in day length and displays a compressed circadian pattern of electrical activity in short winter days and a decompressed pattern in long summer days (2). This pattern is based on a change in the phase distribution of the activity patterns of individual neurons, which becomes broad in the summer and narrow in the winter (3). The mechanisms that mediate and regulate photoperiod-induced phase distributions are currently not known.The neurotransmitter γ-aminobutyric acid (GABA) is believed to be involved in the phase adjustment and synchronization of the SCN neuronal network (4, 5). GABA and its receptors are expressed in most SCN neurons (6). GABAergic inhibition has been indicated to be important in normal physiological function within the brain. Alterations in this system (i.e., less inhibition) are shown to cause neurological disorders, such as epilepsy and autism (7,8). In addition to its classical inhibitory function within the SCN network, GABA has more recently been shown to also act as an excitatory transmitter, although its exact role is uncertain (4, 9-13). To understand the influence of photoperiod on GABAergic function, we studied synaptic activity, using patch clamp, and GABAergic responses, using Ca 2+ imaging techniques, in the SCN of mice adjusted to long-day and short-day photoperiods. We hypothesized that the narrow, synchronized phase distribution of active neurons during short-day photoperiods would result in increased synaptic activity during the day. Surprisingly, however, exposure to a short-day photoperiod decreased the frequency of spontaneous GABAergic synaptic events compared with the long-day photoperiod.Subsequently, we tested the effect of photoperiod on GABAinduced excitation in the SCN neuronal network. Ca 2+ transients were measured in response to GABA stimulation in long-day and short-day photoperiods. Interestingly, of all cells from the long-day photoperiod, 40% were excitatory and 36% were inhibitory. In contrast, in the short-day photoperiod, 28% of the c...

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“…A clinical study done on 60 children showed improvements in some ASD‐related clinical manifestations. Therefore, bumetanide is currently under investigation as a prospective drug by restoring the gradient and GABA inhibition and, thereby, considered as a potential ASD‐therapeutic agent (Lemonnier et al., 2012; Table 3). …”

Section: Reviewmentioning

confidence: 99%

Autism throughout genetics: Perusal of the implication of ion channels

et al. 2018

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BackgroundAutism spectrum disorder (ASD) comprises a group of neurodevelopmental psychiatric disorders characterized by deficits in social interactions, interpersonal communication, repetitive and stereotyped behaviors and may be associated with intellectual disabilities. The description of ASD as a synaptopathology highlights the importance of the synapse and the implication of ion channels in the etiology of these disorders.MethodsA narrative and critical review of the relevant papers from 1982 to 2017 known by the authors was conducted.ResultsGenome‐wide linkages, association studies, and genetic analyses of patients with ASD have led to the identification of several candidate genes and mutations linked to ASD. Many of the candidate genes encode for proteins involved in neuronal development and regulation of synaptic function including ion channels and actors implicated in synapse formation. The involvement of ion channels in ASD is of great interest as they represent attractive therapeutic targets. In agreement with this view, recent findings have shown that drugs modulating ion channel function are effective for the treatment of certain types of patients with ASD.ConclusionThis review describes the genetic aspects of ASD with a focus on genes encoding ion channels and highlights the therapeutic implications of ion channels in the treatment of ASD.

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A randomised controlled trial of bumetanide in the treatment of autism in children

Cited by 255 publications

References 85 publications

KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome

KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome

Seasonal induction of GABAergic excitation in the central mammalian clock

Autism throughout genetics: Perusal of the implication of ion channels

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