Combined low-dose (2R,6R)-Hydroxynorketamine and memantine restore BDNF/TrkB signaling and synaptic function in an LPS-induced model of depressive-like behavior in male mice.

Major depressive disorder (MDD) is increasingly recognized as involving both neuroinflammatory alterations and synaptic pathology. While (2R,6R)-hydroxynorketamine (HNK) exerts rapid antidepressant effects via synaptic modulation, memantine (MEM) shows complementary neuroprotective properties. However, whether their combination offers complementary benefits in inflammation-associated depressive-like phenotypes remains unclear. We investigated MEM combined with low-dose HNK (MEM + 1/2HNK) using an acute LPS-induced model of depressive-like behavior in male mice and primary cortical neuron cultures. Behavioral assessments included sucrose preference test (SPT), forced swim test (FST), tail suspension test (TST), and open field test (OFT). Proteomic profiling, western blotting, immunocytochemistry, and microelectrode array (MEA) recordings were performed. K252a, a broad-spectrum kinase inhibitor commonly used to interfere with Trk receptor-associated signaling, was used to assess the involvement of BDNF/TrkB-related signaling. MEM + 1/2HNK alleviated LPS-induced behavioral deficits in the SPT, FST, and TST, producing effects broadly comparable to full-dose HNK, whereas reduced-dose HNK and MEM alone showed limited efficacy. Proteomic profiling of the medial prefrontal cortex (mPFC) revealed upregulation of glutamatergic synapse and mTOR signaling proteins. MEM + 1/2HNK restored excitatory synapse density and activated the BDNF-TrkB-PI3K-AKT-mTOR signaling pathway in vivo and in vitro. MEA recordings demonstrated that MEM + 1/2HNK reversed LPS-induced disruptions in neuronal network firing rates and synchrony. K252a treatment attenuated the behavioral, synaptic, and electrophysiological improvements induced by MEM + 1/2HNK, supporting the involvement of Trk receptor-associated signaling. Together, these findings suggest that MEM and low-dose HNK counteract inflammation-associated neural dysfunction in association with Trk-related signaling. These proof-of-concept findings do not establish a safety or overall drug-burden advantage over full-dose HNK and require validation in both sexes before translational advantages can be inferred.