title: Age-dependent decrease of GAD65/67 mRNAs but normal densities of GABAergic interneurons in the brain regions of Shank3-overexpressing manic mouse model.
abstract: Dysfunction of inhibitory GABAergic interneurons is considered a major pathophysiological feature of various neurodevelopmental and neuropsychiatric disorders. The variants of SHANK3 gene, encoding a core scaffold protein of the excitatory postsynapse, have been associated with numerous brain disorders. It has been suggested that abnormalities of GABAergic interneurons could contribute to the SHANK3-related disorders, but the limitation of these studies is that they used mainly Shank3 knock-out mice. Notably, Shank3-overexpressing transgenic mice, modeling human hyperkinetic disorders, also show reduced inhibitory synaptic transmission, abnormal electroencephalography, and spontaneous seizures. However, it has not been investigated whether these phenotypes of Shank3 transgenic mice are associated with GABAergic interneuron dysfunction, or solely due to the cell-autonomous postsynaptic changes of principal neurons. To address this issue, we investigated the densities of parvalbumin- and somatostatin-positive interneurons, and the mRNA and protein levels of GAD65/67 GABA-synthesizing enzymes in the medial prefrontal cortex, striatum, and hippocampus of adult Shank3 transgenic mice. We found no significant difference in the measurements performed on wild-type versus Shank3 transgenic mice, except for the decreased GAD65 or GAD67 mRNAs in these brain regions. Interestingly, only GAD65 mRNA was decreased in the hippocampus, but not mPFC and striatum, of juvenile Shank3 transgenic mice which, unlike the adult mice, did not show behavioral hyperactivity. Together, our results suggest age-dependent decrease of GAD65/67 mRNAs but normal densities of certain GABAergic interneurons in the Shank3 transgenic mice.
authors.affiliation: Department of Neuroscience, College of Medicine, Korea University, Seoul 02841, South Korea.
authors.forename: Bokyoung
authors.initials: B
authors.lastname: Lee
authors.affiliation: Department of Neuroscience, College of Medicine, Korea University, Seoul 02841, South Korea; Department of Biomedical Sciences, College of Medicine, Korea University, Seoul 02841, South Korea.
authors.forename: Yinhua
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Neuroscience, College of Medicine, Korea University, Seoul 02841, South Korea.
authors.forename: Yoonhee
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Neuroscience, College of Medicine, Korea University, Seoul 02841, South Korea; Department of Biomedical Sciences, College of Medicine, Korea University, Seoul 02841, South Korea.
authors.forename: Shinhyun
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Neuroscience, College of Medicine, Korea University, Seoul 02841, South Korea; Department of Biomedical Sciences, College of Medicine, Korea University, Seoul 02841, South Korea.
authors.forename: Yeunkum
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Neuroscience, College of Medicine, Korea University, Seoul 02841, South Korea; Department of Biomedical Sciences, College of Medicine, Korea University, Seoul 02841, South Korea. Electronic address: neurohan@korea.ac.kr.
authors.forename: Kihoon
authors.initials: K
authors.lastname: Han
mesh_terms: D000818:Animals; D001714:Bipolar Disorder / Q000201:enzymology*; D001921:Brain / Q000201:enzymology*; D003342:Corpus Striatum / Q000201:enzymology; D004195:Disease Models, Animal; D059330:GABAergic Neurons / Q000201:enzymology*; D005968:Glutamate Decarboxylase / Q000378:metabolism*; D006624:Hippocampus / Q000201:enzymology; D007395:Interneurons / Q000201:enzymology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010320:Parvalbumins / Q000378:metabolism; D017397:Prefrontal Cortex / Q000201:enzymology; D012333:RNA, Messenger / Q000378:metabolism; D013004:Somatostatin / Q000378:metabolism
chemical_list: D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D010320:Parvalbumins; D012333:RNA, Messenger; C492356:Shank3 protein, mouse; D013004:Somatostatin; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; C401141:glutamate decarboxylase 2
keywords: GABAergic interneuron; GAD65; GAD67; Parvalbumin; Shank3