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Neuropharmacology. 2017 Apr;116:387-398. doi: 10.1016/j.neuropharm.2017.01.014. Epub 2017 Jan 17.

Sigma-1 receptor deficiency reduces GABAergic inhibition in the basolateral amygdala leading to LTD impairment and depressive-like behaviors.

Author information

1
State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China; Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
2
Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
3
Department of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 210029, China. Electronic address: wangjun@njmu.edu.cn.
4
Department of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 210029, China.
5
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.

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.

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)

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