title: Sigma-1 receptor deficiency reduces GABAergic inhibition in the basolateral amygdala leading to LTD impairment and depressive-like behaviors.
abstract: Sigma-1 receptor knockout (σ1R-/-) in male mice causes depressive-like phenotype. We observed the expression of σ1R in principal neurons of basolateral amygdala (BLA), a main region for affective regulation. The present study investigated the influence of σ1R deficiency in BLA neurons on synaptic properties and plasticity at cortico-BLA pathway. In comparison with wild-type (WT) mice, the slopes of field excitatory postsynaptic potentials (fEPSP) were reduced in σ1R-/-mice with the increases in paired-pulse facilitation (PPF) and paired-pulse inhibition (PPI) values. Induction of NMDA receptor (NMDAr)-dependent long-term potentiation (LTP) and NMDAr-independent long-term depression (LTD) were impaired in σ1R-/-mice. The NMDAr NR2B phosphorylation in BLA of σ1R-/-mice was lower than in WT mice. The coupling of nNOS to PSD-95 and nitric oxide (NO) level were reduced in BLA of σ1R-/-mice, which were recovered by the BLA-injection of NMDAr agonist NMDA. The bath-application of NMDA in BLA slices from σ1R-/-mice corrected the reduced fEPSP slopes and increased PPF and PPI and recovered the LTP and LTD induction, which were sensitive to nNOS inhibitor 7-NI. NO donor DETA/NO or GABAAR agonist muscimol could correct the PPI and recover LTD in σ1R-/-mice. In addition, the BLA-injection of NMDA, DETA/NO or muscimol could relieve the depressive-like behaviors in σ1R-/-mice. These results indicate that the σ1R deficiency in BLA principal neurons via NMDAr dysfunction suppresses nNOS activity and NO production to reduce GABAAR-mediated inhibition, which impairs LTD induction and causes depressive-like phenotype.
authors.affiliation: State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China; Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Baofeng
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Chen
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Hong
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Sha
authors.initials: S
authors.lastname: Sha
authors.affiliation: Department of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 210029, China. Electronic address: wangjun@njmu.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Hang
authors.initials: H
authors.lastname: Xiao
authors.affiliation: State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China; Department of Physiology, Nanjing Medical University, Nanjing 210029, China. Electronic address: lingchen@njmu.edu.cn.
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D066272:Basolateral Nuclear Complex / Q000187:drug effects / Q000378:metabolism*; D003863:Depression / Q000378:metabolism*; D000076122:Disks Large Homolog 4 Protein / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology*; D008297:Male; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D017480:Receptors, sigma / Q000172:deficiency* / Q000235:genetics; D046509:Tissue Culture Techniques; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; C121001:NR2B NMDA receptor; D018377:Neurotransmitter Agents; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D017480:Receptors, sigma; D009569:Nitric Oxide; D005680:gamma-Aminobutyric Acid; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse
keywords: Basolateral amygdala (BLA); GABA(A) receptor (GABA(A)R); N-methyl-d-aspartate receptor (NMDAr); Sigma-1 receptor (σ(1)R); Synaptic plasticity; neuronal nitric oxide synthase (nNOS)