Multiple Kinases Involved in the Nicotinic Modulation of Gamma Oscillations in the Rat Hippocampal CA3 Area.

Jiangang Wang,Xianglin Cheng,Xiaofang Wang,Fangli Guo,Zhiwei Feng,Martin Vreugdenhil,Xiaolong He,Chengbiao Lu,Yali Wang

doi:10.3389/fncel.2017.00057

Abstract

Neuronal synchronization at gamma band frequency (20–80 Hz, γ oscillations) is closely associated with higher brain function, such as learning, memory and attention. Nicotinic acetylcholine receptors (nAChRs) are highly expressed in the hippocampus, and modulate hippocampal γ oscillations, but the intracellular mechanism underlying such modulation remains elusive. We explored multiple kinases by which nicotine can modulate γ oscillations induced by kainate in rat hippocampal area CA3 in vitro. We found that inhibitors of cyclic AMP dependent kinase (protein kinase A, PKA), protein kinase C (PKC), N-methyl-D-aspartate receptor (NMDA) receptors, Phosphoinositide 3-kinase (PI3K) and extracellular signal-related kinases (ERK), each individually could prevent the γ oscillation-enhancing effect of 1 μM nicotine, whereas none of them affected baseline γ oscillation strength. Inhibition of the serine/threonine kinase Akt increased baseline γ oscillations and partially blocked its nicotinic enhancement. We propose that the PKA-NMDAR-PI3K-ERK pathway modifies cellular properties required for the nicotinic enhancement of γ oscillations, dependent on a PKC-ERK mediated pathway. These signaling pathways provide clues for restoring γ oscillations in pathological conditions affecting cognition. The suppression of γ oscillations at 100 μM nicotine was only dependent on PKA-NMDAR activation and may be due to very high intracellular calcium levels.

Highlights

Hippocampal oscillations reflect the coordinated, rhythmic activity emerging from mutually connected interneuron and principal cell populations
We found that nicotinic modulation of γ oscillation requires both protein kinase A (PKA) and N-methyl-D-aspartate receptors (NMDARs) activity and is partially blocked by protein kinase C (PKC), ERK1/2 and Phosphoinositide 3-kinase (PI3K) inhibitors, suggesting that the NMDAR-PKA signaling pathway plays a critical role whereas PKC, extracellular signal-related kinases (ERK) 1/2 and PI3K play a less critical role in acute nicotinic modulation of hippocampal γ oscillations
We found that activation of a PKA/PKCNMDAR-ERK/PI3K signaling pathway is required for nicotinic enhancement of γ oscillations, with a partial involvement of Akt

Summary

Introduction

Hippocampal oscillations reflect the coordinated, rhythmic activity emerging from mutually connected interneuron and principal cell populations. Γ oscillations are impaired in neuropsychological disorders such as schizophrenia and Alzheimer’s disease which may explain the deficits of working memory in these disorders (Cho et al, 2006; Leicht et al, 2010; Klein et al, 2016). Nicotine induced hippocampal theta oscillations (Lu and Henderson, 2010) and increased the auditory-evoked or the stimulationevoked hippocampal γ oscillations (Song et al, 2005; Featherstone et al, 2012), which may well explain the improvement of cognitive function in both normal subjects and patients with schizophrenia (Phillips et al, 2007). We found that nicotine at a low concentration increases hippocampal γ oscillations induced by kainate in vitro, while at a high concentration, nicotine decreases γ activity (Wang et al, 2015). The intracellular mechanism involved in nicotinic modulation of γ oscillation is unclear

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Conclusion