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

The takeaway

HBK-15, a novel sigma-1 receptor ligand, shows strong potential as a treatment for cognitive deficits linked to glutamatergic dysfunction. By engaging mechanisms that support synaptic plasticity and neural network stability, it effectively reverses memory impairments in animal models mimicking the cognitive symptoms of depression and schizophrenia.

The science

HBK-15 acts on the sigma-1 receptor, a key regulator of neuronal communication and plasticity. In mice with NMDA receptor–related memory deficits resembling those seen in depression and schizophrenia, HBK-15 restored both recognition and spatial memory. These improvements were accompanied by enhanced hippocampal plasticity—stronger synaptic connections and normalized brainwave coordination essential for learning and recall. Blocking sigma-1 receptors prevented the behavioral effects of HBK-15, confirming that its pro-cognitive action depends on this pathway. Unlike standard drugs such as vortioxetine or lurasidone, HBK-15 consistently improved cognitive performance across multiple tests.

Why it matters

By restoring synaptic and network plasticity disrupted by NMDA dysfunction, HBK-15 underscores sigma-1 receptor activation as a promising strategy for cognitive improvement in mood and psychotic disorders.

Orginal article

https://doi.org/10.1016/j.neurot.2025.e00774