Exposure to low-dose CuO nanoparticles improves fear extinction memory and enhance intrinsic excitability in the infralimbic cortex of male mice

Abstract

Abstract Aims: Nanomaterials have gained considerable attention for diverse medical applications, particularly in neurology. Copper oxide nanoparticles (CuO-NPs) exhibit unique nanoscale properties that enable close interactions with neuronal cells, highlighting their potential as therapeutic agents for modulating synaptic plasticity and improving cognitive function. We aimed to investigate whether low-dose CuO-NPs can enhance fear extinction memory and increase intrinsic excitability in the infralimbic cortex (IL) of male mice.

Materials and methods: Adult male mice were subjected to fear conditioning using auditory cues paired with footshocks. Following the administration of a low dose of CuO-NPs, behavioral performance was assessed by measuring freezing responses during extinction. Whole-cell patch-clamp recordings were then performed on IL pyramidal neurons to evaluate intrinsic excitability and AMPA/NMDA ratio. Transmission electron microscopy (TEM) was applied after 2 and 24 h to assess the ability of CuO-NPs to reach the brain.

Key findings: We demonstrated via TEM that CuO-NPs efficiently cross the blood-brain barrier within 24 h' post-administration. Using cued fear conditioning, we subsequently found that a single intraperitoneal injection of CuO-NPs enhanced fear extinction memory, as evidenced by a significant reduction in freezing behavior compared to control animals. Patch-clamp analysis confirmed that CuO-NPs increased the excitability of IL pyramidal neurons and induced a sustained reduction in fast, medium, and slow post-spike after hyperpolarizations. Additionally, we demonstrated that CuO-NPs increased N-methyl-d-aspartate receptor-mediated synaptic currents, suggesting an enhanced synaptic plasticity in the infralimbic cortex.