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Sigma‐1 receptor stimulation by dehydroepiandrosterone ameliorates cognitive impairment through activation of CaM kinase II, protein kinase C and extracellular signal‐regulated kinase in olfactory bulbectomized mice
Author(s) -
Moriguchi Shigeki,
Yamamoto Yui,
Ikuno Tatsuya,
Fukunaga Kohji
Publication year - 2011
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2011.07256.x
Subject(s) - endocrinology , medicine , autophosphorylation , protein kinase c , long term potentiation , neuroactive steroid , protein kinase a , phosphorylation , kinase , biology , chemistry , neuroscience , microbiology and biotechnology , receptor , gabaa receptor
J. Neurochem. (2011) 117 , 879–891. Abstract Dehydroepiandrosterone (DHEA) is one of the most abundant neurosteroids synthesized de novo in the CNS. We here found that sigma‐1 receptor stimulation by DHEA improves cognitive function through phosphorylation of synaptic proteins in olfactory bulbectomized (OBX) mouse hippocampus. We have previously reported that calcium/calmodulin‐dependent protein kinase II (CaMKII), protein kinase C (PKC) and extracellular signal‐regulated kinase (ERK) were impaired in OBX mouse hippocampus. OBX mice were administered once a day for 7–8 days with DHEA (30 or 60 mg/kg p.o.) 10 days after operation. The spatial, cognitive and conditioned fear memories in OBX mice were significantly improved as assessed by Y‐maze, novel object recognition and passive avoidance task, respectively. DHEA also improved impaired hippocampal long‐term potentiation in OBX mice. Notably, DHEA treatment restored PKCα (Ser‐657) autophosphorylation and NR1 (Ser‐896) and myristoylated alanine‐rich protein kinase C substrate (Ser‐152/156) phosphorylation to the control levels in the hippocampal CA1 region. Likewise, DHEA treatment improved CaMKIIα (Thr‐286) autophosphorylation and GluR1 (Ser‐831) phosphorylation to the control levels in the CA1 region. Furthermore, DHEA treatment improved ERK and cAMP‐responsive element‐binding protein (Ser‐133) phosphorylation to the control levels. Finally, NE‐100, sigma‐1 receptor antagonist, significantly inhibited the DHEA‐induced improvement of memory‐related behaviors and CaMKII, PKC and ERK phosphorylation in CA1 region. Taken together, sigma‐1 receptor stimulation by DHEA ameliorates OBX‐induced impairment in memory‐related behaviors and long‐term potentiation in the hippocampal CA1 region through activation of CaMKII, PKC and ERK.