title: Transmembrane protein 108 is required for glutamatergic transmission in dentate gyrus.
abstract: Neurotransmission in dentate gyrus (DG) is critical for spatial coding, learning memory, and emotion processing. Although DG dysfunction is implicated in psychiatric disorders, including schizophrenia, underlying pathological mechanisms remain unclear. Here we report that transmembrane protein 108 (Tmem108), a novel schizophrenia susceptibility gene, is highly enriched in DG granule neurons and its expression increased at the postnatal period critical for DG development. Tmem108 is specifically expressed in the nervous system and enriched in the postsynaptic density fraction. Tmem108-deficient neurons form fewer and smaller spines, suggesting that Tmem108 is required for spine formation and maturation. In agreement, excitatory postsynaptic currents of DG granule neurons were decreased in Tmem108 mutant mice, indicating a hypofunction of glutamatergic activity. Further cell biological studies indicate that Tmem108 is necessary for surface expression of AMPA receptors. Tmem108-deficient mice display compromised sensorimotor gating and cognitive function. Together, these observations indicate that Tmem108 plays a critical role in regulating spine development and excitatory transmission in DG granule neurons. When Tmem108 is mutated, mice displayed excitatory/inhibitory imbalance and behavioral deficits relevant to schizophrenia, revealing potential pathophysiological mechanisms of schizophrenia.
authors.affiliation: Institute of Life Science, Nanchang University, Nanchang 330031, China.|School of Life Sciences, Nanchang University, Nanchang 330031, China.|Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA30912.
authors.forename: Hui-Feng
authors.initials: HF
authors.lastname: Jiao
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA30912.
authors.forename: Xiang-Dong
authors.initials: XD
authors.lastname: Sun
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA30912.
authors.forename: Ryan
authors.initials: R
authors.lastname: Bates
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA30912.
authors.forename: Lei
authors.initials: L
authors.lastname: Xiong
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA30912.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA30912.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA30912.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA30912.
authors.forename: Hong-Sheng
authors.initials: HS
authors.lastname: Zhang
authors.affiliation: Institute of Life Science, Nanchang University, Nanchang 330031, China.
authors.forename: Shun-Qi
authors.initials: SQ
authors.lastname: Wang
authors.affiliation: Institute of Life Science, Nanchang University, Nanchang 330031, China.|School of Life Sciences, Nanchang University, Nanchang 330031, China.
authors.forename: Ming-Tao
authors.initials: MT
authors.lastname: Xiong
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA30912.
authors.forename: Mihir
authors.initials: M
authors.lastname: Patel
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA30912.
authors.forename: Alexis M
authors.initials: AM
authors.lastname: Stranahan
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA30912.|Charlie Norwood Veterans Administration Medical Center, Augusta University, Augusta, GA30912.
authors.forename: Wen-Cheng
authors.initials: WC
authors.lastname: Xiong
authors.affiliation: Institute of Life Science, Nanchang University, Nanchang 330031, China; lmei@augusta.edu bmli@ncu.edu.cn.|Jiangxi Medical School, Nanchang University, Nanchang 330031, China.
authors.forename: Bao-Ming
authors.initials: BM
authors.lastname: Li
authors.affiliation: Institute of Life Science, Nanchang University, Nanchang 330031, China; lmei@augusta.edu bmli@ncu.edu.cn.|Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA30912.|Charlie Norwood Veterans Administration Medical Center, Augusta University, Augusta, GA30912.|Jiangxi Medical School, Nanchang University, Nanchang 330031, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Mei
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D003072:Cognition Disorders / Q000235:genetics* / Q000503:physiopathology; D018891:Dentate Gyrus / Q000378:metabolism / Q000502:physiology*; D004195:Disease Models, Animal; D018274:Electroporation; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005239:Fear; D017930:Genes, Reporter; D018698:Glutamic Acid / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D018782:Maze Learning; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000502:physiology / Q000648:ultrastructure; D057907:Post-Synaptic Density / Q000737:chemistry; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D018091:Receptors, AMPA / Q000096:biosynthesis; D012559:Schizophrenia / Q000235:genetics; D055139:Sensory Gating / Q000235:genetics* / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology; D033921:Vesicular Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D034741:RNA, Small Interfering; D018091:Receptors, AMPA; D033921:Vesicular Transport Proteins; C569742:retrolinkin protein, mouse; D018698:Glutamic Acid
keywords: AMPA receptors; dentate gyrus; glutamatergic transmission; schizophrenia; spine