Male mice hit harder by Parkinson’s-linked depression in new study

Depression is one of the most disabling non-motor features of Parkinson’s disease, yet the biological reasons why some patients are hit harder than others remain poorly mapped. A new study in Frontiers in Pharmacology suggests that sex may be a decisive factor, at least in a widely used animal model of the disorder. Working with adult male and female CD1 mice, researchers found that after a single day of MPTP neurotoxin treatment, males developed stronger depressive- and anxiety-like behaviors and showed deeper molecular disruption in the hippocampus than females, even though both sexes sustained clear damage to the nigrostriatal dopamine system.

The team, based at the Oasi Research Institute in Troina and the University of Messina in Italy, used the MPTP model, in which the toxin’s metabolite MPP+ destroys dopaminergic neurons of the substantia nigra and depletes striatal dopamine terminals. Four groups of ten mice each received either MPTP or vehicle, and fourteen days later the animals were tested for motor-independent mood changes and then euthanized for brain analyses. The authors selected this model because it reliably induces nigrostriatal dysfunction and provides a framework for studying the non-motor side of Parkinson’s disease.

Behavioral testing revealed a consistent pattern. In the forced swim test, both sexes became more immobile than their sham controls, but MPTP-treated males stayed immobile significantly longer than females, an index of stronger behavioral despair. In the light/dark test, males spent less time in the illuminated compartment, and in the sucrose preference test, males showed a marked drop in sucrose consumption, pointing to an anhedonic phenotype. On the elevated plus-maze, MPTP-treated males spent more time in closed arms and in the center and less time in open arms than females. Taken together, the data indicated that male mice are more susceptible to MPTP-induced depressive and anxiety-like behaviors.

The molecular work began with validation of the model itself. Nissl staining and immunohistochemistry showed significant reductions in tyrosine hydroxylase and the dopamine transporter in the substantia nigra pars compacta of MPTP-treated mice of both sexes, alongside significant accumulation of alpha-synuclein. When the two sexes were compared directly, these pathological alterations were slightly more pronounced in males than in females, consistent with the idea that males are more predisposed to Parkinsonian neurodegeneration in this model.

The researchers then turned to neurotransmitter systems linked to mood regulation. Western blotting revealed a significant reduction in the serotonin 5-HT2C receptor in MPTP-treated animals compared with shams, and this reduction was particularly pronounced in males. ELISA measurements showed no change in serum acetylcholine but a significant increase in hippocampal acetylcholine after MPTP exposure, again most notably in males. Because serotonin dysfunction and cholinergic imbalance have both been implicated in the emotional disturbances of Parkinson’s disease, the authors argue that this dual alteration may represent a neurochemical substrate for the more severe depressive phenotype seen in males.

Synaptic integrity in the hippocampus told a similar story. Double immunofluorescence for the postsynaptic scaffolding protein PSD-95 and the presynaptic vesicle protein synaptophysin, each co-labeled with MAP2, showed that MPTP significantly reduced both markers relative to sham groups. The loss was more pronounced in males, while females retained relatively preserved synaptic marker levels. Since PSD-95 and synaptophysin are considered reliable indicators of synaptic connectivity, the findings suggest that MPTP compromises hippocampal plasticity in a sex-dependent way, with males bearing the heavier burden.

The final layer of analysis concerned the BDNF/PI3K/AKT pathway, a molecular cascade that supports neuronal survival, synaptic plasticity and mood. Western blots of hippocampal lysates showed a marked reduction in BDNF levels and decreased activation of PI3K and phosphorylated AKT in MPTP-treated mice of both sexes. Again, the changes were more pronounced in males, whereas females showed partial preservation of neurotrophic signaling. The authors propose that this stronger downregulation in males helps explain their greater vulnerability to depressive-like symptoms in the model.

Importantly, the study’s authors connect these molecular changes rather than treating them as isolated events. Alongside nigrostriatal degeneration, they observed downregulation of the BDNF/PI3K/AKT pathway, which they suggest further compromises neuronal survival and synaptic plasticity, contributing to the reduced expression of PSD-95 and synaptophysin. The greater neurodegenerative burden in male mice may therefore be linked to altered neurotrophic signaling and synaptic integrity, ultimately feeding into the more pronounced depressive- and anxiety-like phenotype.

The authors are careful to note that their findings do not simply mirror clinical observations. Although depressive disorders are generally more prevalent in women in the general population, and some clinical data suggest women with Parkinson’s disease may carry a greater burden of mood-related non-motor symptoms, sex differences seen in patients cannot be directly extrapolated to neurotoxin-based models. Male mice are known to be more susceptible to MPTP-induced dopaminergic toxicity, possibly because of the neuroprotective effects of estrogens, so the stronger behavioral phenotype in males may partly reflect greater vulnerability to the toxin itself rather than to Parkinson’s disease as it occurs in humans.

The study also has other limitations the authors acknowledge. Hormone levels were not directly measured, so the proposed protective role of estrogens remains a hypothesis rather than a demonstrated mechanism, and the MPTP model does not fully reproduce the complexity of Parkinson’s disease in humans. Even so, the authors argue that the results underscore the importance of considering sex as a biological variable in Parkinson’s research and point toward the possibility of developing targeted, sex-specific therapeutic strategies for the non-motor symptoms of the disease, potentially improving quality of life and enhancing the efficacy of conventional antidepressant treatments.

Subject of Research: Sex differences in depressive-like behavior and related molecular changes in a mouse model of Parkinson's disease

Article Title: Gender differences in depressive-like behavior in Parkinson’s disease

Article References: Deborah, M., Laura, C., Rossella, B., Davide, L., Emanuela, E., Michela, C., & Irene, P. (2026). Gender differences in depressive-like behavior in Parkinson’s disease. Frontiers in Pharmacology, 17, Article 1961464. https://doi.org/10.3389/fphar.2026.1961464

Image Credits: AI Generated

DOI: 10.3389/fphar.2026.1961464

Keywords: Parkinson's disease, depression, MPTP mouse model, sex differences, 5-HT2C receptor, acetylcholine, PSD-95, synaptophysin, BDNF/PI3K/AKT pathway, hippocampus, alpha-synuclein, substantia nigra