Roles of GSK3β in Odor Habituation and Spontaneous Neural Activity of the Mouse Olfactory Bulb

Zhixiang Xu,Fuqiang Xu,Guo Chen,Xiaoping Rao,Li Wang,Nadine Ravel

doi:10.1371/journal.pone.0063598

Abstract

Glycogen synthase kinase 3β (GSK3β), a multifaceted kinase, is abundantly expressed in the brain, including the olfactory bulb (OB). In resting cells, GSK3β is constitutively active, and its over-activation is presumably involved in numerous brain diseases, such as Alzheimer’s disease. However, the functions of the constitutively active GSK3β in the adult brain under physiological conditions are not well understood. Here, we studied the possible functions of GSK3β activity in the OB. Odor stimulation, or blockade of peripheral olfactory inputs caused by either transgenic knock-out or ZnSO4 irrigation to the olfactory epithelium, all affected the expression level of GSK3β in the OB. When GSK3β activity was reduced by a selective inhibitor, the spontaneous oscillatory activity was significantly decreased in the granule cell layer of the OB. Furthermore, local inhibition of GSK3β activity in the OB significantly impaired the odor habituation ability. These results suggest that GSK3β plays important roles in both spontaneous neural activity and odor information processing in the OB, deepening our understanding of the potential functions of the constitutively active GSK3β in the brain under physiological conditions.

Highlights

Glycogen synthase kinase 3b (GSK3b), a conserved serine/ threonine protein kinase, that is abundantly expressed in the mammalian brain [1,2]
Using immunohistochemistry (IHC), we found that the signal of total-GSK3b (TGSK3b) in the olfactory bulb (OB) of CNGX mice was remarkably decreased in the mitral cell and granule cell layers (Fig. 1A–B)
We found that the power of spontaneous baseline activity (1–90 Hz) in the OB was significantly decreased (Fig. 4C, D and E, P,0.001, 16 mice), after the animals were treated with TDZD-8, a specific inhibitor of GSK3b activity [27], while the spontaneous neural activity in the vehicle-treated mice was not altered (Fig. 4A, B and E, P = 0.685, 10 mice)

Summary

Introduction

Glycogen synthase kinase 3b (GSK3b), a conserved serine/ threonine protein kinase, that is abundantly expressed in the mammalian brain [1,2] The activity of this kinase is primarily regulated by phosphorylation. GSK3b is essential for activity-dependent bulk endocytosis of synaptic vesicles during elevated neural activity through rephosphorylation of Dynamin I [4] Consistent with this observation, it has been reported that GSK3b is involved in the regulation of the two major forms of synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD) [5,6,7]. We altered the activity of GSK3b by using its specific inhibitor and found that the spontaneous neural activity in the OB was significantly decreased and that the odor cross-habituation behavior was significantly impaired These results demonstrated that this kinase is involved in more general neural processes, providing evidences why its dys-regulation could lead to a variety of brain diseases

Results

Discussion

Materials and Methods