Intracellular copper regulates olfactory transmission through neuroplasticity and mitochondrial function in olfactory bulb granule cells

Copper is essential for central nervous system function; however, its role in olfaction remains unclear. Here, the contribution of copper to olfactory transmission was investigated by examining its effects on neuronal activity. Systemic brain copper deficiency or selective copper deficiency in olfactory bulb (OB) granule cells impaired olfactory function in C57BL/6J mice. In the OB, copper deficiency altered neuroplasticity-related signaling and reduced the structural plasticity of granule cells. Copper deficiency also reduced mitochondrial complex IV activity and induced mitochondrial swelling in OB granule cells, with similar mitochondrial dysfunction observed in vitro. Notably, olfactory dysfunction in mice with brain-specific copper transporter 1 (<i>Ctr1</i>) deficiency was improved by restoring copper levels or re-establishing <i>Ctr1</i> expression in granule cells. These findings indicate that copper in OB granule cells supports olfactory function by maintaining neuroplasticity and mitochondrial activity.