Sex differences of synaptic plasticity and microglial remodeling in the dorsal hippocampus following trigeminal nerve injury in mice

Peripheral nerve injury patients have chronic pain as well as poor memory and cognitive functioning that is associated with hippocampal abnormalities. Despite sex-dependent changes in the hippocampus of patients with chronic pain, detailed sex differences in hippocampal plasticity after peripheral nerve injury are not well known. In mice with infraorbital nerve chronic constriction injury (ION-CCI), we found complex sex differences in the dorsal hippocampus (dHC). ION-CCI suppressed population spikes amplitude and long-term potentiation (LTP) in the dHC compared to sham group, which was consistent in females but not males. The field excitatory postsynaptic potential was comparable between sexes in the sham group, and ION-CCI suppressed it in both sexes. Short-term facilitation after paired-pulse protocol was also comparable between the sexes in the sham group but was only suppressed in males with ION-CCI. While microglial numbers in the dHC were comparable between the sexes, the proportion of hyper-ramified microglia was higher in males in the sham group. ION-CCI increased the total number of microglia in both sexes; however, the proportion of hyper-ramified microglia was increased by ION-CCI in females only. In novel object recognition tests, female mice exhibited better object recognition memory than males in the sham group, which was impaired by ION-CCI. Taken together, these results suggest that female mice exhibit stronger object recognition in the uninjured condition, which may be related to stronger hippocampal synaptic functions and potentiation. Furthermore, trigeminal nerve injury may produce a greater effect on synaptic functions and plasticity, along with cognitive deficits, in females.