title: GABAergic synaptic inputs of locus coeruleus neurons in wild-type and Mecp2-null mice.
abstract: Rett syndrome is an autism spectrum disorder resulting from defects in the gene encoding the methyl-CpG-binding protein 2 (MeCP2). Deficiency of the Mecp2 gene causes abnormalities in several systems in the brain, especially the norepinephrinergic and GABAergic systems. The norepinephrinergic neurons in the locus coeruleus (LC) modulate a variety of neurons and play an important role in multiple functions in the central nervous system. In Mecp2(-/Y) mice, defects in the intrinsic membrane properties of LC neurons have been identified, while how their synaptic inputs are affected remains unclear. Therefore, we performed these brain slice studies to demonstrate how LC neurons are regulated by GABAergic inputs and how such synaptic inputs are affected by Mecp2 knockout. In whole cell current clamp, the firing activity of LC neurons was strongly inhibited by the GABAA receptor agonist muscimol, accompanied by hyperpolarization and a decrease in input resistance. Such a postsynaptic inhibition was significantly reduced (by ~30%) in Mecp2(-/Y) mice. Post- and presynaptic GABABergic inputs were found in LC neurons, which were likely mediated by the G protein-coupled, Ba(2+)-sensitive K(+) channels. The postsynaptic GABABergic inhibition was deficient by ~50% in Mecp2 knockout mice. Although the presynaptic GABABergic modulation appeared normal, both frequency and amplitude of the GABAAergic mIPSCs were drastically decreased (by 30-40%) in Mecp2-null mice. These results suggest that the Mecp2 disruption causes defects in both post- and presynaptic GABAergic systems in LC neurons, impairing GABAAergic and GABABergic postsynaptic inhibition and decreasing the GABA release from presynaptic terminals.
authors: Department of Biology, Georgia State University, Atlanta, GA 30302-4010, USA.
authors: Xin
authors: X
authors: Jin
authors: Ningren
authors: N
authors: Cui
authors: Weiwei
authors: W
authors: Zhong
authors: Xiao-Tao
authors: XT
authors: Jin
authors: Chun
authors: C
authors: Jiang
mesh_terms: D000818:Animals; D001418:Baclofen / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D058786:GABA-B Receptor Agonists / Q000494:pharmacology; D059330:GABAergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008125:Locus Coeruleus / Q000473:pathology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009118:Muscimol / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D017729:Presynaptic Terminals / Q000502:physiology; D011963:Receptors, GABA-A / Q000378:metabolism; D018080:Receptors, GABA-B / Q000378:metabolism; D015518:Rett Syndrome / Q000235:genetics / Q000473:pathology; D013570:Synaptic Membranes / Q000378:metabolism* / Q000502:physiology; D009435:Synaptic Transmission; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D018756:GABA Antagonists; D058785:GABA-A Receptor Agonists; D058786:GABA-B Receptor Agonists; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; C052329:phaclofen; D009118:Muscimol; D005680:gamma-Aminobutyric Acid; D001418:Baclofen
keywords: GABAergic; Rett syndrome; brainstem; locus coeruleus; noradrenaline
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