Loss of Brain-Derived Neurotrophic Factor and Sex-Specific Disruption of Neuronal Function

Brain-Derived Neurotrophic Factor (BDNF) is considered one of the most influential neurotrophins in the brain. It has known involvement in synaptic signaling and interaction with estrogen in the brain (E2) to perform neuroprotective functions. Although previous studies have examined the role of BDNF under pathologic conditions, the detailed molecular interactions that mediate BDNF action in the adult brain remain incompletely explored. In this study, we used protein expression analyses of hippocampal tissue to examine the effects of whole-brain BDNF knockdown (BDNF+/- KD) on the expression of various synaptic markers and estrogen receptors in otherwise healthy male and female rats. Relative to wildtype (WT) controls, only the BDNF+/- KD males showed increased levels of the presynaptic marker, synaptophysin, while exhibiting a decrease in the postsynaptic marker, PSD-95. Glutamatergic and cholinergic neuronal markers were not significantly changed in both the male and female rats after BDNF loss. BDNF+/- KD males also show a uniform upregulation in estrogen receptor expression, including ER-α, ER-β, and GPER1, which remained unchanged in the females. Taken together, our results suggest that BDNF loss leads to disruptions in synaptic signaling mechanisms in a sex-specific manner, and these sex differences may reflect the actions of estrogen receptors in the hippocampus. In conclusion, our study contributes to the understanding of sex differences in BDNF signaling in the brain. This will aid in development of novel therapeutic targets for various neuropsychiatric and neurodegenerative disorders, including the natural process of aging, where BDNF is a known player.