Hyperforin modulates dendritic spine morphology in hippocampal pyramidal neurons by activating Ca²⁺‐permeable TRPC6 channels

Abstract

The standardized extract of the St. John’s wort plant (Hypericum perforatum) is commonly used to treat mild to moderate depression. Its active constituent is hyperforin, a phloroglucinol derivative that reduces the reuptake of serotonin and norepinephrine by increasing intracellular Na+ concentration through the activation of non-selective cationic TRPC6 channels. TRPC6 channels are also Ca2+-permeable, resulting in intracellular Ca2+ elevations. Indeed, hyperforin activates TRPC6-mediated currents and Ca2+ transients in rat PC12 cells, which induce their differentiation, mimicking the neurotrophic effect of NGF. Here, we show that hyperforin modulates dendritic spine morphology in CA1 and CA3 pyramidal neurons of hippocampal slice cultures through the activation of TRPC6 channels. Hyperforin also evoked intracellular Ca2+ transients and depolarizing inward currents sensitive to the TRPC channel blocker La3+, thus resembling the actions of the neurotrophin BDNF in hippocampal pyramidal neurons. These results suggest that the antidepressant actions of St. John’s wort are mediated by a mechanism similar to that engaged by BDNF.

The mechanisms of action of St. John’s wort: an update

“…Hyperforin evoked intracellular Ca 2 + transients and depolarizing inward currents sensitive to the TRPC channel blocker La 3+ , thus resembling the actions of the neurotrophin brain-derived neurotrophic factor (BDNF) in hippocampal pyramidal neurons. These results suggest that the antidepressant actions of SJW might be mediated by a mechanism similar to that engaged by BDNF [23].…”

The Use of Induced Pluripotent Stem Cell Technology to Advance Autism Research and Treatment

“…Previously unassociated with ASD, TRPC6 is a voltage-independent, Ca 2+ -permeable cation channel. TRPC6 has been implicated in neuronal growth cone guidance, spinogenesis, and synaptogenesis, processes known to be affected in ASD [117][118][119]. Furthermore, TRPC6 has been shown to activate important pathways important for neuronal development and function, including the brain-derived neurotrophic factor (BDNF), calcium/calmodulin-dependent protein kinase IV, protein kinase B, and cyclic adenosine monophosphate-response element binding protein phosphorylation signaling pathways (Fig.…”

Ca2+ signaling initiated by canonical transient receptor potential channels in dendritic development

“…is required for proper growth-cone turning in response to microscopic gradients of netrin-1; and TRPC5 and 6 play different roles in regulating dendritic development [18][19][20][21] .…”