Hyperexcitability of Mesencephalic Trigeminal Neurons and Reorganization of Ion Channel Expression in a Rett Syndrome Model

Oginsky, Max F.; Cui, Ningren; Zhong, Weiwei; Johnson, Christopher M.; Jiang, Chun

doi:10.1002/jcp.25589

Cited by 19 publications

(19 citation statements)

References 67 publications

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“…Our results have shown that Me5 neurons are also hyperexcitable (Oginsky et al. ). The Me5 neurons are the only group of propriosensory neurons with soma located in the CNS, which provide servo feedback control to the jaw muscles.…”

Section: Discussionsupporting

confidence: 71%

“…; Oginsky et al. ). Suppression of overly excited Me5 neurons may lead to a correction in the proprioception of muscles, leading to the improvement of motor function in RTT.…”

Section: Discussionmentioning

confidence: 97%

“…; Oginsky et al. ), which may contribute to the difficulties in chewing and eating in people with RTT (Isaacs et al. ; Motil et al.…”

Section: Introductionmentioning

confidence: 99%

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Effects of early‐life exposure to THIP on brainstem neuronal excitability in the Mecp2‐null mouse model of Rett syndrome before and after drug withdrawal

Zhong

Johnson

Cui

et al. 2017

Physiological Reports

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Rett syndrome (RTT) is mostly caused by mutations of the X‐linked MECP2 gene. Although the causal neuronal mechanisms are still unclear, accumulating experimental evidence obtained from Mecp2 −/Y mice suggests that imbalanced excitation/inhibition in central neurons plays a major role. Several approaches may help to rebalance the excitation/inhibition, including agonists of GABAA receptors (GABAAR). Indeed, our previous studies have shown that early‐life exposure of Mecp2‐null mice to the extrasynaptic GABAAR agonist THIP alleviates several RTT‐like symptoms including breathing disorders, motor dysfunction, social behaviors, and lifespan. However, how the chronic THIP affects the Mecp2 −/Y mice at the cellular level remains elusive. Here, we show that the THIP exposure in early lives markedly alleviated hyperexcitability of two types of brainstem neurons in Mecp2 −/Y mice. In neurons of the locus coeruleus (LC), known to be involved in breathing regulation, the hyperexcitability showed clear age‐dependence, which was associated with age‐dependent deterioration of the RTT‐like breathing irregularities. Both the neuronal hyperexcitability and the breathing disorders were relieved with early THIP treatment. In neurons of the mesencephalic trigeminal nucleus (Me5), both the neuronal hyperexcitability and the changes in intrinsic membrane properties were alleviated with the THIP treatment in Mecp2‐null mice. The effects of THIP on both LC and Me5 neuronal excitability remained 1 week after withdrawal. Persistent alleviation of breathing abnormalities in Mecp2 −/Y mice was also observed a week after THIP withdrawal. These results suggest that early‐life exposure to THIP, a potential therapeutic medicine, appears capable of controlling neuronal hyperexcitability in Mecp2 −/Y mice, which occurs in the absence of THIP in the recording solution, lasts at least 1 week after withdrawal, and may contribute to the RTT‐like symptom mitigation.

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Section: Discussionsupporting

confidence: 71%

“…; Oginsky et al. ). Suppression of overly excited Me5 neurons may lead to a correction in the proprioception of muscles, leading to the improvement of motor function in RTT.…”

Section: Discussionmentioning

confidence: 97%

See 1 more Smart Citation

Effects of early‐life exposure to THIP on brainstem neuronal excitability in the Mecp2‐null mouse model of Rett syndrome before and after drug withdrawal

Zhong

Johnson

Cui

et al. 2017

Physiological Reports

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“…Several research groups have reported elevated basal activity and augmented neuronal response to electrical stimulation, in RTT syndrome models [ 16 – 18 ]. We asked how enhanced vulnerability in RTT is expressed in respiratory alkalosis and which role the surface potential plays.…”

Section: Introductionmentioning

confidence: 99%

Rescue of hyperexcitability in hippocampal CA1 neurons from Mecp2 (-/y) mouse through surface potential neutralization

Balakrishnan¹,

Mironov²

2018

PLoS ONE

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Hyperventilation is a known feature of Rett syndrome (RTT). However, how hyperventilation is related to other RTT symptoms such as hyperexcitability is unknown. Intense breathing during hyperventilation induces hypocapnia and culminates in respiratory alkalosis. Alkalinization of extracellular milieu can trigger epilepsy in patients who already have neuronal hyperexcitability. By combining patch-clamp electrophysiology and quantitative glutamate imaging, we compared excitability of CA1 neurons of WT and Mecp2 (-/y) mice, and analyzed the biophysical properties of subthreshold membrane channels. The results show that Mecp2 (-/y) CA1 neurons are hyperexcitable in normal pH (7.4) and are increasingly vulnerable to alkaline extracellular pH (8.4), during which their excitability increased further. Under normal pH conditions, an abnormal negative shift in the voltage-dependencies of HCN (hyperpolarization-activated cyclic nucleotide-gated) and calcium channels in the CA1 neurons of Mecp2 (-/y) mice was observed. Alkaline pH also enhanced excitability in wild-type (WT) CA1 neurons through modulation of the voltage dependencies of HCN- and calcium channels. Additionally alkaline pH augmented spontaneous glutamate release and burst firing in WT CA1 neurons. Conversely, acidic pH (6.4) and 8 mM Mg2+ exerted the opposite effect, and diminished hyperexcitability in Mecp2 (-/y) CA1 neurons. We propose that the observed effects of pH and Mg2+ are mediated by changes in the neuronal membrane surface potential, which consecutively modulates the gating of HCN and calcium channels. The results provide insight to pivotal cellular mechanisms that can regulate neuronal excitability and help to devise treatment strategies for hyperexcitability induced symptoms of Rett syndrome.

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“…As a result, the balance of excitation vs inhibition becomes abnormal as shown in RTT mouse models. Several groups of brainstem neurons show excessive excitability, while low excitability is found in the neocortex (Calfa et al, 2015; Dani et al, 2005; Oginsky et al, 2016; Zhong et al, 2015). The imbalance in inhibition/excitation may explain some pathophysiology of the RTT-like symptoms.…”

Section: Abnormities In Neurotransmitter Systemsmentioning

confidence: 99%

Breathing abnormalities in animal models of Rett syndrome a female neurogenetic disorder

Jiang

Cui

Zhong

et al. 2017

Respiratory Physiology & Neurobiology

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A characteristic feature of Rett syndrome (RTT) is abnormal breathing accompanied by several other neurological and cognitive disorders. Since RTT rodent models became available, studies have begun shedding insight into the breathing abnormalities at behavioral, cellular and molecular levels. Defects are found in several groups of brainstem neurons involved in respiratory control, and potential neural mechanisms have been suggested. The findings in animal models are helpful in therapeutic strategies for people with RTT with respect to lowering sudden and unexpected death, preventing secondary developmental consequences, and improving the quality of lives.

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Hyperexcitability of Mesencephalic Trigeminal Neurons and Reorganization of Ion Channel Expression in a Rett Syndrome Model

Cited by 19 publications

References 67 publications

Effects of early‐life exposure to THIP on brainstem neuronal excitability in the Mecp2‐null mouse model of Rett syndrome before and after drug withdrawal

Effects of early‐life exposure to THIP on brainstem neuronal excitability in the Mecp2‐null mouse model of Rett syndrome before and after drug withdrawal

Rescue of hyperexcitability in hippocampal CA1 neurons from Mecp2 (-/y) mouse through surface potential neutralization

Breathing abnormalities in animal models of Rett syndrome a female neurogenetic disorder

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