Stimulation of the Sigma-1 Receptor by DHEA Enhances Synaptic Efficacy and Neurogenesis in the Hippocampal Dentate Gyrus of Olfactory Bulbectomized Mice

Abstract

Dehydroepiandrosterone (DHEA) is the most abundant neurosteroid synthesized de novo in the central nervous system. We previously reported that stimulation of the sigma-1 receptor by DHEA improves cognitive function by activating calcium/calmodulin-dependent protein kinase II (CaMKII), protein kinase C and extracellular signal-regulated kinase in the hippocampus in olfactory bulbectomized (OBX) mice. Here, we asked whether DHEA enhances neurogenesis in the subgranular zone of the hippocampal dentate gyrus (DG) and improves depressive-like behaviors observed in OBX mice. Chronic treatment with DHEA at 30 or 60 mg/kg p.o. for 14 days significantly improved hippocampal LTP impaired in OBX mice concomitant with increased CaMKII autophosphorylation and GluR1 (Ser-831) phosphorylation in the DG. Chronic DHEA treatment also ameliorated depressive-like behaviors in OBX mice, as assessed by tail suspension and forced swim tests, while a single DHEA treatment had no affect. DHEA treatment also significantly increased the number of BrdU-positive neurons in the subgranular zone of the DG of OBX mice, an increase inhibited by treatment with NE-100, a sigma-1 receptor antagonist. DHEA treatment also significantly increased phosphorylation of Akt (Ser-473), Akt (Ser-308) and ERK in the DG. Furthermore, GSK-3β (Ser-9) phosphorylation increased in the DG of OBX mice possibly accounting for increased neurogenesis through Akt activation. Finally, we confirmed that DHEA treatment of OBX mice increases the number of BrdU-positive neurons co-expressing β-catenin, a downstream GSK-3βtarget. Overall, we conclude that sigma-1 receptor stimulation by DHEA ameliorates OBX-induced depressive-like behaviors by increasing neurogenesis in the DG through activation of the Akt/GSK-3β/β-catenin pathway.

Stimulation of Sigma-1 Receptor Ameliorates Depressive-like Behaviors in CaMKIV Null Mice

“…Depressive-Like Behavioral Tasks (1) Tail suspension task: A detailed protocol of this task is described [8]. The test is based on the fact that normally, animals exhibit immobile posture when subjected to short-term, inescapable stress by tail suspension.…”

“…The test is based on the fact that normally, animals exhibit immobile posture when subjected to short-term, inescapable stress by tail suspension. (2) Forced swim task: The forced swim task is described elsewhere [8]. Mice are placed individually in glass cylinders (height, 20 cm; diameter, 15 cm) filled with 25°C water and the duration of immobile periods within a 5-min test is scored.…”

“…Immunohistochemistry Immunohistochemistry was performed as described [8,30]. Mice at 10-12 weeks of age were anesthetized with sevoflurane and perfused via the ascending aorta with phosphate-buffered saline (PBS; pH 7.4) until the outflow became clear.…”

“…Knockout mice lacking Sig-1R exhibit depressive-like behaviors [6]. We also recently reported that impaired cognitive-related and depressive-like behaviors in olfactory bulbectomized mice are improved by chronic oral administration of dehydroepiandrosterone (DHEA), an endogenous Sig-1R ligand [7,8].…”

Memory Improvement by Yokukansankachimpihange and Atractylenolide III in the Olfactory Bulbectomized Mice

“…The administration of YKH (1000 mg/kg) and Aen-III (1.0, 3.0 mg/kg) significantly restored the decreased CaMKII autophosphorylation (OBX YKH: 105.6% ± 5.7%, n = 8; OBX Aen-III 1.0 mg/kg: 96.1% ± 8.0%, n = 8; OBX Aen-III 3.0 mg/kg: 100.4% ± 3.0%, n = 8) (Figure 3(a) and Figure 3(b)). Additionally, we previously documented that CaMKIV and CREB phosphorylation drastically decreased in OBX mice [11] [23]. We next examined the effects of YKH and Aen-III for CaMKIV/CREB signaling.…”