Abstract
Activin A is known as a neuroprotective factor produced upon acute excitotoxic injury of the hippocampus (in pathological states). We attempt to reveal the role of activin as a neuromodulator in the adult male hippocampus under physiological conditions (in healthy states), which remains largely unknown. We showed endogenous/basal expression of activin in the hippocampal neurons. Localization of activin receptors in dendritic spines (=postsynapses) was demonstrated by immunoelectron microscopy. The incubation of hippocampal acute slices with activin A (10 ng/mL, 0.4 nM) for 2 h altered the density and morphology of spines in CA1 pyramidal neurons. The total spine density increased by 1.2-fold upon activin treatments. Activin selectively increased the density of large-head spines, without affecting middle-head and small-head spines. Blocking Erk/MAPK, PKA, or PKC prevented the activin-induced spinogenesis by reducing the density of large-head spines, independent of Smad-induced gene transcription which usually takes more than several hours. Incubation of acute slices with activin for 2 h induced the moderate early long-term potentiation (moderate LTP) upon weak theta burst stimuli. This moderate LTP induction was blocked by follistatin, MAPK inhibitor (PD98059) and inhibitor of NR2B subunit of NMDA receptors (Ro25-6981). It should be noted that the weak theta burst stimuli alone cannot induce moderate LTP. These results suggest that MAPK-induced phosphorylation of NMDA receptors (including NR2B) may play an important role for activin-induced moderate LTP. Taken together, the current results reveal interesting physiological roles of endogenous activin as a rapid synaptic modulator in the adult hippocampus.
Highlights
Activin A is a homodimer of inhibin βA polypeptides, which belongs to the superfamily of transforming growth factor-β (TGF-β) (Pangas and Woodruff, 2000)
We examined the role of activin in an acute effect on adult rat hippocampus under physiological conditions
To date much effort has been devoted to investigate the role of activin as neuroendocrinological factor in hypothalamic-pituitary-gonadal (HPG) axis (Ling et al, 1986; Vale et al, 1986; Gregory and Kaiser, 2004) or neuroprotective factor in excitotoxic injury (Tretter et al, 1996, 2000)
Summary
Activin A is a homodimer of inhibin βA polypeptides, which belongs to the superfamily of transforming growth factor-β (TGF-β) (Pangas and Woodruff, 2000). Activin binds to type II receptor (Ser/Thr kinase receptor) and dimerization of type II and type I receptors occurs, resulting in phosphorylation the Smad family transcription factors, which leads to gene expression (Pangas and Woodruff, 2000; Derynck and Zhang, 2003). Activin is essential in the neuroprotective action following acute excitotoxic lesion of the hippocampus (Tretter et al, 1996, 2000). A significant elevation of the expression of mRNA of activin is demonstrated in the dentate gyrus (DG) of the hippocampus upon excitotoxic high frequency stimulation (Inokuchi et al, 1996) or after acute injury (Lai et al, 1996, 1997; Tretter et al, 1996, 2000)
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