Requirement of sigma-1 receptor (Sig-1R) for boosting the gamma oscillations in the medial prefrontal cortex (mPFC)

Background and purpose: Gamma oscillations have emerged as a promising biomarker of depression, but the underlying molecular mechanism remains unknown. Sigma-1 receptors (Sig-1R) have attracted increasing interest, and this study aims to investigate their role in regulating gamma oscillations.

Experimental approach: Electrophysiological recordings and calcium signal recordings in freely walking mice were used to record the dynamic changes of neural activities in response to drug treatments. SSRIs with varying affinities for Sig-1R and AAV virus for overexpression were used to pharmacologically and genetically manipulate Sig-1Rs.

Key results: SA4503 (a selective Sig-1R agonist, 3 mg·kg^-1, i.p.) significantly increased firing rates and CA²⁺ signals of pyramidal neurons and gamma oscillations in the medial prefrontal cortex (mPFC), but paroxetine (low affinity for Sig-1R among SSRIs, 10 mg·kg^-1, i.p.) has no such effects under the same conditions. Conversely, fluvoxamine (high affinity for Sig-1R among SSRIs, 30 mg·kg^-1, i.p.), significantly increased firing rates and CA²⁺ signals of pyramidal neurons and gamma oscillations, and these electrophysiological properties were reversed by BD1047 (a selective Sig-1R antagonist, 3 mg·kg^-1, i.p.). In addition, our results showed that BD1047 blocked the enhancement in gamma oscillations induced by Ro 10-5824 (3 mg·kg^-1, i.p.); Sig-1R overexpression greatly increased firing rates and CA²⁺ signals of pyramidal neurons and gamma oscillations.

Conclusion and implications: We propose the important role of Sig-1R in modulating gamma oscillations, and SSRIs displayed varying abilities to boost gamma oscillations in the mPFC based on their affinity for Sig-1R, which yields new insights into the molecular mechanism underlying gamma oscillations.