title: Temporal- and Location-Specific Alterations of the GABA Recycling System in Mecp2 KO Mouse Brains.
abstract: Rett syndrome (RTT), associated with mutations in methyl-CpG-binding protein 2 (Mecp2), is linked to diverse neurological symptoms such as seizures, motor disabilities, and cognitive impairments. An altered GABAergic system has been proposed as one of many underlying pathologies of progressive neurodegeneration in several RTT studies. This study for the first time investigated the temporal- and location-specific alterations in the expression of γ-amino butyric acid (GABA) transporter 1 (GAT-1), vesicular GABA transporter (vGAT), and glutamic acid decarboxylase 67kD (GAD67) in wild type (WT) and knockout (KO) mice in the Mecp2(tm1.1Bird/y) mouse model of RTT. Immunohistochemistry (IHC) co-labeling of GAT-1 with vGAT identified GABAergic synapses that were quantitated for mid-sagittal sections in the frontal cortex (FC), hippocampal dentate gyrus (DG), and striatum (Str). An age-dependent increase in the expression of synaptic GABA transporters, GAT-1, and vGAT, was observed in the FC and DG in WT brains. Mecp2 KO mice showed a significant alteration in this temporal profile that was location-specific, only in the FC. GAD67-positive cell densities also showed an age-dependent increase in the FC, but a decrease in the DG in WT mice. However, these densities were not significantly altered in the KO mice in the regions examined in this study. Therefore, the significant location-specific downregulation of synaptic GABA transporters in Mecp2 KO brains with unaltered densities of GAD67-positive interneurons may highlight the location-specific synaptic pathophysiology in this model of RTT.
authors.affiliation: Neuroscience Laboratory, Hugo Moser Research Institute at Kennedy Krieger.
authors.forename: Seok K
authors.initials: SK
authors.lastname: Kang
authors.affiliation: Neuroscience Laboratory, Hugo Moser Research Institute at Kennedy Krieger.
authors.forename: Shin Tae
authors.initials: ST
authors.lastname: Kim
authors.affiliation: Neuroscience Laboratory, Hugo Moser Research Institute at Kennedy Krieger. ; Departments of Neurology, Johns Hopkins University School of Medicine; Baltimore, USA. ; Department of Pediatrics, Johns Hopkins University School of Medicine; Baltimore, USA.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Johnston
authors.affiliation: Neuroscience Laboratory, Hugo Moser Research Institute at Kennedy Krieger. ; Departments of Neurology, Johns Hopkins University School of Medicine; Baltimore, USA.
authors.forename: Shilpa D
authors.initials: SD
authors.lastname: Kadam
keywords: GABAergic neurons; GAT-1; MeCP2 mutation; Rett syndrome; lipofuscin; synapse
references.citation: Front Cell Neurosci. 2011 Apr 05;5:2
references.pmid: 21503156
references.citation: J Physiol. 2009 May 1;587(Pt 9):1873-9
references.pmid: 19153158
references.citation: Anat Rec (Hoboken). 2011 Oct;294(10):1624-34
references.pmid: 21901842
references.citation: Nat Neurosci. 2000 Oct;3(10):998-1003
references.pmid: 11017172
references.citation: Neuroscience. 2006;139(4):1449-60
references.pmid: 16549272
references.citation: IUBMB Life. 2009 May;61(5):522-7
references.pmid: 19391165
references.citation: J Neurochem. 2008 Jun;105(5):1781-93
references.pmid: 18248614
references.citation: Pediatr Neurol. 2013 May;48(5):337-45
references.pmid: 23583050
references.citation: Brain Dev. 2005 Nov;27 Suppl 1:S77-S87
references.pmid: 16182491
references.citation: Acta Neuropathol. 1988;76(2):142-58
references.pmid: 2900587
references.citation: Neuropsychopharmacology. 2010 Jan;35(1):147-68
references.pmid: 19794405
references.citation: BMC Neurosci. 2010 Feb 17;11:19
references.pmid: 20163734
references.citation: BMC Neurosci. 2010 Apr 26;11:53
references.pmid: 20420693
references.citation: Nat Genet. 2005 Jan;37(1):31-40
references.pmid: 15608638
references.citation: J Physiol. 2013 May 15;591(10):2429-41
references.pmid: 23381899
references.citation: Development. 2002 Jan;129(1):245-52
references.pmid: 11782417
references.citation: Neuron. 2013 Feb 6;77(3):388-405
references.pmid: 23395369
references.citation: Neuron. 2007 Nov 8;56(3):422-37
references.pmid: 17988628
references.citation: J Neurophysiol. 2010 May;103(5):2470-81
references.pmid: 20200124
references.citation: Nature. 2011 Jun 29;475(7357):497-500
references.pmid: 21716289
references.citation: J Neurophysiol. 2008 Jan;99(1):112-21
references.pmid: 18032561
references.citation: Nat Neurosci. 2007 Dec;10(12):1513-4
references.pmid: 17994015
references.citation: Nat Neurosci. 2010 Sep;13(9):1120-7
references.pmid: 20711185
references.citation: J Neurochem. 2004 Apr;89(1):204-16
references.pmid: 15030405
references.citation: Front Cell Neurosci. 2013 Nov 15;7:208
references.pmid: 24298237
references.citation: Nature. 2010 Nov 11;468(7321):263-9
references.pmid: 21068835
references.citation: Biol Psychiatry. 2006 Mar 1;59(5):468-76
references.pmid: 16199017
references.citation: Neurosci Biobehav Rev. 2012 Oct;36(9):2044-55
references.pmid: 22841562
references.citation: J Comp Neurol. 1998 May 4;394(2):252-69
references.pmid: 9552130