Abnormal Expression of Cerebrospinal Fluid Cation Chloride Cotransporters in Patients with Rett Syndrome

Duarte, Sofia; Armstrong, Judith; Roche, Ana; Ortez, C.; Perez, Ana Paula da Silva; O’Callaghan, María del Mar; Pereira, Antonina; Sanmartí, Francesc; Ormazábal, Aída; Artuch, Rafael; Pineda, Mercédes; García‐Cazorla, Àngels

doi:10.1371/journal.pone.0068851

Cited by 77 publications

(68 citation statements)

References 33 publications

(44 reference statements)

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“…A recent clinical trial with bumetanide, a commonly used diuretic that inhibits NKCC1 function, demonstrated improvement in clinical scores for autism patients, suggesting that NKCC1 function may be upregulated in autism and may be a causal factor in some of the behavioral disruptions associated with autism (Lemonnier et al, 2012). In addition, a recent study that analyzed protein concentration in the CSF of Rett syndrome patients demonstrated an upregulation in the ratio of NKCC1 to KCC2, further suggesting that alterations in chloride transporters might be a general finding in neurodevelopmental disorders linked with autism (Duarte et al, 2013). Our results are the first to describe the maintenance of a depolarized E Cl-in the cortex to later developmental time points and a change in the relative expression of the chloride cotransporters in the cortex of the mouse model of fragile X syndrome.…”

Section: Discussionmentioning

confidence: 99%

The Developmental Switch in GABA Polarity Is Delayed in Fragile X Mice

et al. 2014

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Delays in synaptic and neuronal development in the cortex are key hallmarks of fragile X syndrome, a prevalent neurodevelopmental disorder that causes intellectual disability and sensory deficits and is the most common known cause of autism. Previous studies have demonstrated that the normal progression of plasticity and synaptic refinement during the critical period is altered in the cortex of fragile X mice. Although the disruptions in excitatory synapses are well documented in fragile X, there is less known about inhibitory neurotransmission during the critical period. GABAergic transmission plays a crucial trophic role in cortical development through its early depolarizing action. At the end of cortical critical period, response properties of GABA transform into their mature hyperpolarizing type due to developmental changes in intracellular chloride homeostasis. We found that the timing of the switch from depolarizing to hyperpolarizing GABA is delayed in the cortex of fragile X mice and there is a concurrent alteration in the expression of the neuronal chloride cotransporter NKCC1 that promotes the accumulation of intracellular chloride. Disruption of the trophic effects of GABA during cortical development could contribute to the altered trajectory of synaptic maturation in fragile X syndrome.

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Section: Discussionmentioning

confidence: 99%

The Developmental Switch in GABA Polarity Is Delayed in Fragile X Mice

et al. 2014

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“…Increased intracellular chloride concentration and a change in the postsynaptic impact of GABAergic synapses have been demonstrated during development in mouse models of ASD, including fragile-X syndrome (23,24). Indirect evidence also points to this mechanism affecting RTT: Lower levels of KCC2 relative to NKCC1 have been found by immunoblot analysis of cerebrospinal fluid samples in patients with RTT (25); depolarizing GABAergic synapses in development follow from down-regulation of brain-derived neurotrophic factor (BDNF) (26), which is also an early consequence of MeCP2 deletion in mouse models (27); and insulin-like growth factor-1 (IGF1) treatment, which partially rescues behavioral and synaptic deficits in mutant mouse models of RTT (28,29), also activates KCC2 expression and restores the inhibitory action of GABAergic synapses in the hippocampus (30). Thus, the diverse effects of MeCP2 loss may include reducing inhibition via changes in GABA-mediated hyperpolarization.…”

Section: Significancementioning

confidence: 99%

Jointly reduced inhibition and excitation underlies circuit-wide changes in cortical processing in Rett syndrome

Banerjee

Rikhye

Breton-Provencher

et al. 2016

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

151

202

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Rett syndrome (RTT) arises from loss-of-function mutations in methyl-CpG binding protein 2 gene (Mecp2), but fundamental aspects of its physiological mechanisms are unresolved. Here, by whole-cell recording of synaptic responses in MeCP2 mutant mice in vivo, we show that visually driven excitatory and inhibitory conductances are both reduced in cortical pyramidal neurons. The excitation-to-inhibition (E/I) ratio is increased in amplitude and prolonged in time course. These changes predict circuit-wide reductions in response reliability and selectivity of pyramidal neurons to visual stimuli, as confirmed by two-photon imaging. and increases KCC2 expression to normalize the KCC2/NKCC1 ratio. Thus, loss of MeCP2 in the brain alters both excitation and inhibition in brain circuits via multiple mechanisms. Loss of MeCP2 from a specific interneuron subtype contributes crucially to the cell-specific and circuit-wide deficits of RTT. The joint restoration of inhibition and excitation in cortical circuits is pivotal for functionally correcting the disorder.MeCP2 | E/I balance | parvalbumin neurons | IGF1 | chloride transporters S ynaptic excitation (E) and inhibition (I), along with the neuronal balance of excitation and inhibition (E/I), is key to the function of brain circuits, and is often disrupted in neurodevelopmental disorders, including autism spectrum disorders (ASDs) (1-3). Rett syndrome (RTT) is a severe neurodevelopmental and adult disorder that arises from sporadic loss-of-function mutations in the X-linked (Xq28) methyl-CpG binding protein 2 gene (Mecp2) encoding the protein MeCP2 (4-7). MeCP2 is a critical regulator of brain development and adult neural function (8), and arrested brain maturation due to synaptic dysfunction is one of the hallmarks of RTT (3). However, the effects of MeCP2 on excitatory and inhibitory synaptic mechanisms in vivo, and on neuronal and circuit function underlying RTT pathophysiology, are unknown.MeCP2 is ubiquitously expressed in multiple cell types and subregions of the brain (4, 6, 9), including inhibitory interneurons, and has cell-autonomous as well as non-cell-autonomous effects (10); thus, it has been particularly challenging to identify its role in cell-specific brain circuits. Anatomically diverse inhibitory interneuron subtypes with distinct physiological signatures influence different aspects of neocortical function and behavior (11,12). Soma-targeting parvalbumin-expressing (PV + ) and dendritetargeting somatostatin-expressing (SOM + ) interneurons are the two major nonoverlapping populations of interneurons in mice that target cortical pyramidal neurons (13). Inhibition by PV + and SOM + neurons powerfully influences neuronal responses and circuit computations in visual cortex (14-17). Deletion of MeCP2 from all forebrain GABAergic interneurons recapitulates key aspects of RTT (18), demonstrating that altered inhibitory function is an important facet of RTT pathophysiology. Indeed, a major phenotype of MeCP2 reduction in individuals with RTT and in mouse models is ...

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“…More recently, analysis of chloride co-transporters in the cerebrospinal fluid of young Rett syndrome patients showed decreased KCC2 protein expression and decreased KCC2/ NKCC1 ratio, reminiscent of immature GABA A receptor function (Duarte et al, 2013) (Figure 1).…”

Section: Rett Syndromementioning

confidence: 99%

The GABAA Receptor as a Therapeutic Target for Neurodevelopmental Disorders

Braat

Kooy

2015

Neuron

248

210

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Intellectual disability, autism spectrum disorder, and epilepsy are prime examples of neurodevelopmental disorders that collectively affect a significant percentage of the world population. Recent technological breakthroughs allowed the elucidation of the genetic causes of many of these disorders. As neurodevelopmental disorders are genetically heterogeneous, the development of rational therapy is extremely challenging. Fortunately, many causative genes are interconnected and cluster in specific cellular pathways. Targeting a common node in such a network would allow us to interfere with a series of related neurodevelopmental disorders at once. Here, we argue that the GABAergic system is disturbed in many neurodevelopmental disorders, including fragile X syndrome, Rett syndrome, and Dravet syndrome, and is a key candidate target for therapeutic intervention. Many drugs that modulate the GABAergic system have already been tested in animal models with encouraging outcomes and are readily available for clinical trials.

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Abnormal Expression of Cerebrospinal Fluid Cation Chloride Cotransporters in Patients with Rett Syndrome

Cited by 77 publications

References 33 publications

The Developmental Switch in GABA Polarity Is Delayed in Fragile X Mice

The Developmental Switch in GABA Polarity Is Delayed in Fragile X Mice

Jointly reduced inhibition and excitation underlies circuit-wide changes in cortical processing in Rett syndrome

The GABAA Receptor as a Therapeutic Target for Neurodevelopmental Disorders

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