CALFA GASTON DIEGO
Congresos y reuniones científicas
Título:
The TRPC6 channel activator hyperforin increases dendritic spine density and activates a membrane current associated with Ca2+ elevations in hippocampal CA1 pyramidal neurons
Autor/es:
K. TREIBER, M. AMARAL, S. RUDOLPH, G. CALFA, L. POZZO-MILLER
Lugar:
Chicago
Reunión:
Congreso; Society for Neuroscience - Neuroscience 2009; 2009
Resumen:
TRPC6 channels belong to the family of transient receptor potential channels (TRP) and are highly expressed in the CNS, especially in the hippocampus. However, their role in hippocampal neurons is poorly understood, despite the potential contribution to membrane depolarization and intracellular Ca2+ levels of these nonselective cationic channels. Intriguingly, genetic deletion of TRPC6 in hippocampal CA1 neurons caused dendritic spine loss in hippocampal CA1 pyramidal neurons. Since we identified TRPC3 channels as downstream effectors of BDNF-induced dendritic spine formation, membrane currents and Ca2+ signals, and TRPC3 and TRPC6 channels are known to form heteromultimers, we studied the effects of hyperforin, a known activator of TRPC6 channels. Hyperforin is the main active ingredient in St. John s wort, which has been used for centuries as an herbal alternative to treat mood disorders. A single brief (30 sec) and localized
application of hyperforin (1.5 μM) activated a slowly developing inward current associated with intracellular Ca2+ elevations in voltage-clamped CA1 pyramidal neurons (at -65mV and Cs+-loaded cells in the presence of TTX). These responses were not observed in neurons expressing a shRNA designed to knockdown TRCP6 expression. In addition, hyperforin increased the proportion of mature dendritic in CA1 and CA3 pyramidal neurons, without affecting overall spine density. This spinogenic effect of hyperforin was also prevented by shRNA-mediated knockdown, and mimicked by TRPC6 overexpression. Our results demonstrate that hyperforin is an activator of TRPC6 channels in CA1 pyramidal neurons, where its effects are similar to those of the neurotrophin BDNF. Thus, TRPC3/6 channels are potential novel targets of antidepressant drug development, and hyperforin and related structures seem suitable BDNF mimetic compounds that cross the blood-brain barrier.
application of hyperforin (1.5 μM) activated a slowly developing inward current associated with intracellular Ca2+ elevations in voltage-clamped CA1 pyramidal neurons (at -65mV and Cs+-loaded cells in the presence of TTX). These responses were not observed in neurons expressing a shRNA designed to knockdown TRCP6 expression. In addition, hyperforin increased the proportion of mature dendritic in CA1 and CA3 pyramidal neurons, without affecting overall spine density. This spinogenic effect of hyperforin was also prevented by shRNA-mediated knockdown, and mimicked by TRPC6 overexpression. Our results demonstrate that hyperforin is an activator of TRPC6 channels in CA1 pyramidal neurons, where its effects are similar to those of the neurotrophin BDNF. Thus, TRPC3/6 channels are potential novel targets of antidepressant drug development, and hyperforin and related structures seem suitable BDNF mimetic compounds that cross the blood-brain barrier.
