Imagine your brain as a bustling city with different pathways and channels that help messages travel. In perimenopausal depression, one such pathway called the BDNF-TRPC6 signaling pathway experiences some troubles. It turns out that estradiol (E2), a form of estrogen, can come to the rescue! Scientists have discovered that E2 has neuroprotective effects by boosting the levels of brain-derived neurotrophic factor (BDNF) and transient receptor potential channels 6 (TRPC6) in the hippocampus, an area of the brain involved in mood regulation. These two molecules help promote neuronal development and strengthen the connections between nerve cells. In a rat model of perimenopausal depression, researchers found that reducing E2 levels led to lower BDNF and TRPC6 levels, as well as increased neuronal death and decreased synaptic connections. However, administering E2 reversed these effects, increasing BDNF and TRPC6 levels, enhancing neuronal survival, and boosting synaptic connections. These findings suggest that the protective effects of estrogen in perimenopausal depression may involve activating the BDNF-TRPC6 pathway. Understanding how hormones and signaling pathways interact in the brain could lead to new strategies for preventing and treating perimenopausal depression. To learn more about this exciting research, check out the full article!

Estradiol (E2) has been proven to be effective in treating perimenopausal depression (PD); however, the downstream signaling pathways have not been fully elucidated. Transient receptor potential channels 6 (TRPC6) plays a vital role in promoting neuronal development and the formation of excitatory synapses. At present, we found that the serum levels of E2 and brain-derived neurotrophic factor (BDNF) declined significantly in the women with PD compared to perimenopausal women, which was accompanied by a clear reduction in TRPC6 levels. To further reveal the effects of TRPC6 on neuronal survival and excitability, the PD-like rat model was established by the total removal of left ovary and 80% removal of right ovary followed by 21 days of the chronic unpredictable mild stress. Intragastric administration of E2 (2 mg/kg), intraperitoneal injection of BDNF/TrB signaling pathway inhibitor (K252a, 100 μg/kg) and TRPC6 agonist (OAG, 0.6 mg/kg), and intracerebroventricular infusion of anti-BDNF antibody for blocking BDNF (0.5 μg/24 μl/rat) daily for 21 days were conducted. The levels of BDNF and TRPC6 in rat serum were lower in PD rats compared to the control rats; the depression-like behavior was induced, the neuronal death rate in the hippocampus increased, and the thickness of postsynaptic density (PSD) and the number of asymmetric synapses decreased significantly in the PD group. E2 treatment greatly upregulated the serum levels of BDNF and TRPC6, the neuronal excitability indicated by an elevation in the PSD thickness and the numbers of asymmetric synapses, and these actions were reversed by K252a; co-administration of TRPC6 agonist and K252a improved neuronal degeneration and increased the neuronal excitability induced in the E2-treated PD rats. K252a or anti-BDNF antibody inhibited the increased neuronal BDNF and TRPC6 expression in E2-treated PD rats; co-treatment of TRPC6 agonist and anti-BDNF antibody reduced neuronal death and increased the BDNF and TRPC6 expression in the hippocampal CA1 neurons in the E2-treated PD rats. These results suggest that the neuroprotective role of E2 in PD is closely related to enhance the activity of BDNF/TRPC6 pathway and is helpful to provide new prevention and strategies.

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