Lentinan produces a robust antidepressant-like effect via enhancing the prefrontal Dectin-1/AMPA receptor signaling pathway

• Lentinan treatment led to a robust antidepressant-like effect in the tail suspension test and forced swim test after 60 min of treatment in mice.
• Dectin-1, the receptor of lentinan, mediated the antidepressant-like effects of lentinan.
• The prefrontal Dectin-1/AMPA receptor signaling pathway was essential for the robust antidepressant-like effects evoked by lentinan.

Lentinan (LNT) is an immune regulator and its potential and mechanism for the treatment of mood disorder is of our interest. Dectin-1 is a β-glucan (including LNT) receptor that regulates immune functions in many immune cell types. Cumulative evidence has suggested that the glutamatergic system seems to play an important role in the treatment of depression. Here, we studied the antidepressant-like effects of LNT and its therapeutical target in regulating the functions of AMPA receptors. We found that 60 min treatment with LNT leads to a significant antidepressant-like effect in the tail suspension test (TST) and the forced swim test (FST) in mice. The antidepressant-like effects of LNT in TST and FST remained after 1 day or 5 days of injections. Additionally, LNT did not show a hyperactive effect in the open field test. Dectin-1 receptor levels were increased after LNT treatment for 5 days and the specific Dectin-1 inhibitor laminarin was able to block the antidepressant-like effects of LNT. After 5 days of treatment, LNT enhanced p-GluR1 (S845) in the prefrontal cortex (PFC); however, the total GluR1, GluR2, and GluR3 expression levels remained unchanged. We also found that the AMPA-specific blocker GYKI 52466 was able to block the antidepressant-like effects of LNT. This study identified LNT as a novel antidepressant with clinical potential and a new antidepressant mechanism for regulating prefrontal Dectin-1/AMPA receptor signaling.