Effects of chronic exposure to THIP on brainstem neuronal excitability in a female mouse model of Rett syndrome

Abstract

Rett Syndrome (RTT) is a neurodevelopmental disease with ~ 0.01% morbidity rate in live‐born girls worldwide. Mutations of MECP2 gene encoding methyl CpG binding protein 2 (MeCP2) underlies over 90% of RTT cases clinically. One of the characteristic features of the disease is defective autonomic function, showing breathing instability, gastrointestinal disorders and cardiac arrhythmia. Imbalanced neuron excitation/inhibition ratio may underlie the development of the symptoms. In Mecp2−/Y mice, several groups of brainstem neurons show excessive excitability, which may contribute to the instability of neuronal networks for the autonomic function. One way to control the neuronal hyperexcitability is to enhance the GABAergic inhibition. We have previously reported that THIP (Gaboxadol), an extrasynaptic GABAA receptor agonist, relieved many RTT‐like symptoms in a male mouse model of RTT. However, several questions are still open as to what the THIP effects are at the cellular level, whether increased excitability of brainstem neurons also occurs in female Mecp2+/− mice, how the mosaic expression of MeCP2 affects the neuronal excitability, and how the MeCP2 expression affects neuronal responses to THIP. Thus, we performed studies to address these questions. After symptomatic Mecp2+/− (sMecp2+/−) female mice were identified with a two‐step screening method, the mice were divided into THIP and vehicle groups. Whole‐cell recording was performed in brain slices from the mice with a prior 5‐week exposure to low‐dose THIP or vehicle. Neurons in the locus coeruleus (LC) and the mesencephalic trigeminal nucleus (Me5) showed excessive firing activity in the vehicle‐treated sMecp2+/− mice. When the effect of mosaic expression of MeCP2 on neuronal hyperexcitability was studied in identified LC cells, we found that the level of hyperexcitability was similar in LC neurons with and without MeCP2 expression. THIP pretreatment stabilized the hyperexcitability of both LC and Me5 neurons of sMecp2+/− mice to a level similar to their WT counterparts. The THIP exposure also suppressed the excessive firing activity of MeCP2‐positive and MeCP2‐negative LC neurons, suggesting that the THIP effects appeared to be determined by not only the MeCP2 expression, but also cellular environmental cues. The alleviation of LC neuronal hyperexcitability seems to benefit brainstem autonomic function as THIP also improved breathing abnormalities of these sMecp2+/− mice.Support or Funding InformationThis work was supported by National Institutes of Health [grant number R01‐NS‐073875] and Brain and Behavior fellowship at Georgia State University.