Loss of MeCP2 in Parvalbumin-and Somatostatin-Expressing Neurons in Mice Leads to Distinct Rett Syndrome-like Phenotypes

Ito-Ishida, Aya; Ure, Kerstin; Chen, Hongmei; Swann, John W.; Zoghbi, Huda Y.

doi:10.1016/j.neuron.2015.10.029

Cited by 151 publications

(191 citation statements)

References 38 publications

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“…Loss of MeCP2 from a subset of forebrain GABAergic neurons recapitulates diverse and prominent features of RTT (18), and the behavioral symptoms of MeCP2 loss can be explained by PV-or SOM-specific MeCP2 deletion (55). Furthermore, interneuron-specific reexpression of MeCP2 can ameliorate some of the deficits seen in RTT (19,75).…”

Section: Discussionmentioning

confidence: 88%

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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.

159

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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Section: Discussionmentioning

confidence: 88%

“…Thus, we restricted our analysis of PV-cKO animals to ages P60 and older. Mice with interneuron-specific deletion of MeCP2 showed several key behavioral phenotypes that are observed in gKO mice or in mice with MeCP2 deletion in selective forebrain GABAergic neurons (55).…”

Section: Mecp2 Deletion From Inhibitory Interneuron Subtypes Alters Imentioning

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.

159

202

View full text Add to dashboard Cite

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“…The mechanisms of epilepsy in Rett syndrome, based on MECP2 deficit, generally support an imbalance of excitation and inhibition, and have been speculated to include multiple specific neuronal cell types, as well as non-cell-autonomous effects of glial cells. Neuronal cell types implicated include forebrain excitatory pyramidal neurons, and inhibitory interneurons, including the somatostatin positive type, and some results are in direct conflict between studies (Zhang et al, 2014;Calfa et al, 2015;Ito-Ishida et al, 2015). Other publications have found no clear difference in neuronal excitability in Mecp2-null mice (McLeod et al, 2013).…”

Section: Discussionmentioning

confidence: 97%

Longitudinal course of epilepsy in Rett syndrome and related disorders

Tarquinio

Hou

Berg

et al. 2016

Brain

100

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Epilepsy is common in Rett syndrome, an X-linked dominant disorder caused by mutations in the MECP2 gene, and in Rett-related disorders, such as MECP2 duplication. However, neither the longitudinal course of epilepsy nor the patterns of seizure onset and remission have been described in Rett syndrome and related conditions. The present study summarizes the findings of the Rett syndrome Natural History study. Participants with clinical Rett syndrome and those with MECP2 mutations without the clinical syndrome were recruited through the Rett Natural History study from 2006 to 2015. Clinical details were collected, and cumulative lifetime prevalence of epilepsy was determined using the Kaplan-Meier estimator. Risk factors for epilepsy were assessed using Cox proportional hazards models. Of 1205 participants enrolled in the study, 922 had classic Rett syndrome, and 778 of these were followed longitudinally for 3939 person-years. The diagnosis of atypical Rett syndrome with a severe clinical phenotype was associated with higher prevalence of epilepsy than those with classic Rett syndrome. While point prevalence of active seizures ranged from 30% to 44%, the estimated cumulative lifetime prevalence of epilepsy using Kaplan-Meier approached 90%. Specific MECP2 mutations were not significantly associated with either seizure prevalence or seizure severity. In contrast, many clinical features were associated with seizure prevalence; frequency of hospitalizations, inability to walk, bradykinesia, scoliosis, gastrostomy feeding, age of seizure onset, and late age of diagnosis were independently associated with higher odds of an individual having epilepsy. Aggressive behaviour was associated with lower odds. Three distinct patterns of seizure prevalence emerged in classic Rett syndrome, including those who did not have seizures throughout the study, those who had frequent relapse and remission, and those who had relentless seizures. Although 248 of those with classic Rett syndrome and a history of seizures were in terminal remission at last contact, only 74 (12% of those with a history of epilepsy) were seizure free and off anti-seizure medication. When studied longitudinally, point prevalence of active seizures is relatively low in Rett syndrome, although lifetime risk of epilepsy is higher than previously reported. While daily seizures are uncommon in Rett syndrome, prolonged remission is less common than in other causes of childhood onset epilepsy. Complete remission off anti-seizure medications is possible, but future efforts should be directed at determining what factors predict when withdrawal of medications in those who are seizure free is propitious.

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“…In tuberous sclerosis, conditional deletion of Tsc1 in astrocytes, excitatory neurons, or inhibitory neurons all results in seizure in mice (Bateup et al, 2013; Fu et al, 2012; Uhlmann et al, 2002). 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).…”

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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Loss of MeCP2 in Parvalbumin-and Somatostatin-Expressing Neurons in Mice Leads to Distinct Rett Syndrome-like Phenotypes

Cited by 151 publications

References 38 publications

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

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

Longitudinal course of epilepsy in Rett syndrome and related disorders

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

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