Gardiquimod, a TLR7 agonist, reverses chronic stress-induced depression in mice via microglia-dependent BDNF signaling

Pharmacological restoration of microglial homeostasis in the hippocampus is emerging as a promising strategy for treating depression. Current antidepressant therapies often have delayed onset, limited efficacy, and significant side effects, highlighting an urgent need for novel mechanisms. Microglial dysfunction, particularly in the hippocampus, contributes to neuroinflammation and impaired neurogenesis, key factors in mood disorders. This study investigates whether targeting Toll-like receptor 7 (TLR7), a pattern recognition receptor, can modulate microglial activity to produce antidepressant effects.

Researchers subjected mice to chronic unpredictable stress (CUS) to induce depression-related behaviors. They then administered a single intraperitoneal (IP) injection of Gardiquimod (GDQ) at 0.5, 1, or 1.5 mg/kg. Behavioral tests were conducted at various time points (5h, 8h, 7 days, 14 days) to assess antidepressant efficacy. Mechanistic studies involved pharmacological inhibition of microglia with minocycline or genetic depletion using PLX3397. Further investigations included intra-hippocampal infusion of a BDNF-neutralizing antibody, genetic disruption of activity-dependent BDNF release via the Val68Met knock-in mutation, and pharmacological blockade of the TrkB receptor with K252a to elucidate the role of BDNF signaling.

A single IP injection of Gardiquimod at 1 or 1.5 mg/kg, but not 0.5 mg/kg, significantly improved depression-related behaviors within 5 hours of administration. Time-course analyses revealed that the antidepressant efficacy of GDQ (1.5 mg/kg) appeared between 5 and 8 hours, persisted for up to 7 days, and diminished by 14 days. Notably, a second GDQ injection at 14 days fully restored the behavioral improvements, indicating sustained responsiveness. Mechanistically, the antidepressant effects of GDQ were completely abolished by both pharmacological inhibition (minocycline) and genetic depletion (PLX3397) of microglia. Furthermore, GDQ reversed the CUS-induced reduction in brain-derived neurotrophic factor (BDNF) protein levels in the dentate gyrus in a microglia-dependent manner. The critical role of BDNF signaling was confirmed as its neutralization, genetic disruption of its release, or TrkB receptor blockade (with K252a) each abolished the behavioral effects of GDQ.