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 GABA_AR 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 GABA_AR-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).