title: Early-Life Social Isolation-Induced Depressive-Like Behavior in Rats Results in Microglial Activation and Neuronal Histone Methylation that Are Mitigated by Minocycline.
abstract: Early-life stress is a potent risk factor for development of psychiatric conditions such as depression. The underlying mechanisms remain poorly understood. Here, we used the early-life social isolation (ESI) model of early-life stress in rats to characterize development of depressive-like behavior, the role of microglia, levels of histone methylation, as well as expression of glutamate receptor subunits in the hippocampus. We found that depressive-like behavior was induced after ESI as determined by sucrose preference and forced swimming tests. Increased expression of microglial activation marker, Iba1, was observed in the hippocampus of the ESI group, while expression of the microglial CD200 receptor, which promotes microglial quiescence, significantly decreased. In addition, increased levels of proinflammatory cytokines, interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF-α) were observed in the hippocampus of the ESI group. Moreover, ESI increased levels of neuronal H3K9me2 (a repressive marker of transcription) and its associated "writer" enzymes, G9a and G9a-like protein, in the hippocampus. ESI also decreased expression of hippocampal NMDA receptor subunits, NR1, and AMPA receptor subunits, GluR1 and GluR2, which are involved in synaptic plasticity, but it did not affect expression of PSD95 and NR2B. Interestingly, treatment with minocycline to block microglial activation induced by ESI inhibited increases in hippocampal microglia and prevented ESI-induced depressive-like behavior as well as increases in IL-1β, IL-6, and TNF-α. Notably, minocycline also triggered downregulation of H3K9me2 expression and restored expression of NR1, GluR1, and GluR2. These results suggest that ESI induces depressive-like behavior, which may be mediated by microglial signaling.
authors.affiliation: Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Tongzipo Road 172, Changsha, Hunan, 410013, China.
authors.forename: Hong-Tao
authors.initials: HT
authors.lastname: Wang
authors.affiliation: Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Tongzipo Road 172, Changsha, Hunan, 410013, China.
authors.forename: Fu-Lian
authors.initials: FL
authors.lastname: Huang
authors.affiliation: Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Tongzipo Road 172, Changsha, Hunan, 410013, China.
authors.forename: Zhao-Lan
authors.initials: ZL
authors.lastname: Hu
authors.affiliation: Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Tongzipo Road 172, Changsha, Hunan, 410013, China.
authors.forename: Wen-Juan
authors.initials: WJ
authors.lastname: Zhang
authors.affiliation: Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Tongzipo Road 172, Changsha, Hunan, 410013, China.
authors.forename: Xiao-Qing
authors.initials: XQ
authors.lastname: Qiao
authors.affiliation: Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Tongzipo Road 172, Changsha, Hunan, 410013, China.
authors.forename: Yan-Qing
authors.initials: YQ
authors.lastname: Huang
authors.affiliation: Department of Anesthesia, the Second XiangYa Hospital, Central South University, Ren-Min Road 86, Changsha, Hunan, China.
authors.forename: Ru-Ping
authors.initials: RP
authors.lastname: Dai
authors.affiliation: Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Tongzipo Road 172, Changsha, Hunan, 410013, China. fangli@csu.edu.cn.
authors.forename: Fang
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Tongzipo Road 172, Changsha, Hunan, 410013, China. changqili@csu.edu.cn.
authors.forename: Chang-Qi
authors.initials: CQ
authors.lastname: Li
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003863:Depression / Q000378:metabolism*; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D005518:Food Preferences / Q000187:drug effects; D006624:Hippocampus / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D046353:Immobility Response, Tonic / Q000187:drug effects; D053583:Interleukin-1beta / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000378:metabolism*; D008911:Minocycline / Q000494:pharmacology*; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012934:Social Isolation / Q000523:psychology*
chemical_list: D002135:Calcium-Binding Proteins; D016207:Cytokines; D000076122:Disks Large Homolog 4 Protein; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D008911:Minocycline; D018091:Receptors, AMPA; D011971:Receptors, Immunologic; D016194:Receptors, N-Methyl-D-Aspartate; C100745:Aif1 protein, rat; C495490:Cd200 protein, rat; C501449:Dlg4 protein, rat; C409466:NR1 NMDA receptor; C121001:NR2B NMDA receptor; C577330:Ehmt2 protein, rat; C104722:glutamate receptor ionotropic, AMPA 2
keywords: Depressive-like behavior; Early-life social isolation; H3K9me2; Microglia; Minocycline