Defective GABAergic neurotransmission in the nucleus tractus solitarius in Mecp2-null mice, a model of Rett syndrome

Chao-Yin Chen, Jacopo Di Lucente, Yen Chu Lin, Cheng Chang Lien, Michael A Rogawski, Izumi Maezawa, Lee-Way Jin

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Rett syndrome (RTT) is a devastating neurodevelopmental disorder caused by loss-of-function mutations in the X-linked methyl-CpG binding protein 2 (Mecp2) gene. GABAergic dysfunction has been implicated contributing to the respiratory dysfunction, one major clinical feature of RTT. The nucleus tractus solitarius (NTS) is the first central site integrating respiratory sensory information that can change the nature of the reflex output. We hypothesized that deficiency in Mecp2 gene reduces GABAergic neurotransmission in the NTS. Using whole-cell patch-clamp recordings in NTS slices, we measured spontaneous inhibitory postsynaptic currents (sIPSCs), miniature IPSCs (mIPSCs), NTS-evoked IPSCs (eIPSCs), and GABAA receptor (GABAA-R) agonist-induced responses. Compared to those from wild-type mice, NTS neurons from Mecp2-null mice had significantly (p < 0.05) reduced sIPSC amplitude, sIPSC frequency, and mIPSC amplitude but not mIPSC frequency. Mecp2-null mice also had decreased eIPSC amplitude with no change in paired-pulse ratio. The data suggest reduced synaptic receptor-mediated phasic GABA transmission in Mecp2-null mice. In contrast, muscimol (GABAA-R agonist, 0.3–100 μM) and THIP (selective extrasynaptic GABAA-R agonist, 5 μM) induced significantly greater current response in Mecp2-null mice, suggesting increased extrasynaptic receptors. Using qPCR, we found a 2.5 fold increase in the delta subunit of the GABAA-Rs in the NTS in Mecp2-null mice, consistent with increased extrasynaptic receptors. As the NTS was recently found required for respiratory pathology in RTT, our results provide a mechanism for NTS dysfunction which involves shifting the balance of synaptic/extrasynaptic receptors in favor of extrasynaptic site, providing a target for boosting GABAergic inhibition in RTT.

Original languageEnglish (US)
Pages (from-to)25-32
Number of pages8
JournalNeurobiology of Disease
Volume109
DOIs
StatePublished - Jan 1 2018

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Keywords

  • Extrasynaptic receptors
  • GABA
  • NTS
  • Patch clamp
  • Rett syndrome

ASJC Scopus subject areas

  • Neurology

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