Sigma-1-targeting multimodal compound HBK-15 reverses memory deficits and restores hippocampal plasticity under NMDA hypofunction

Memory impairment is among the most disabling features of depression and schizophrenia, yet remains largely untreated by available pharmacotherapies. NMDA receptor hypofunction is strongly implicated in these deficits, while sigma-1 receptors, by stabilizing calcium signaling and supporting glutamatergic plasticity, have emerged as a promising therapeutic target. HBK-15, a methoxyphenylpiperazine derivative with a multimodal receptor profile, had previously shown preliminary anti-amnesic activity in rodents, prompting us to test its efficacy under NMDA receptor hypofunction. We therefore investigated whether HBK-15 engages sigma-1 receptors and restores memory in a mouse model of MK-801-induced impairment. HBK-15 bound sigma-1 receptors with high affinity and showed functional agonist activity in the BiP assay. Behaviorally, HBK-15 reversed MK-801-induced recognition and spatial memory deficits across acquisition and retrieval phases, similar to encoding and delayed recall in clinical settings. In contrast, vortioxetine and lurasidone showed only limited benefits, highlighting the broader effectiveness of HBK-15. Its ability to reverse memory impairment depended on sigma-1 receptor activity, emphasizing this pathway as a key therapeutic target. Mechanistically, HBK-15 increased hippocampal glutamatergic and cholinergic signaling under NMDA blockade, restored long-term potentiation, and improved disrupted theta-gamma coupling, a network correlate of hippocampal memory function. These findings offer experimental evidence that HBK-15 activates sigma-1 receptors to enhance hippocampal plasticity at both synaptic and network levels and to improve memory under NMDA hypofunction. Taken together, our results highlight sigma-1-based strategies as a tractable avenue for developing treatments targeting cognitive symptoms in depression and schizophrenia.