Abnormal circadian oscillation of hippocampal MAPK activity and power spectrums in NF1 mutant mice

Lei Chen,Guang He,Shuai Wang,Xu Zhang,Lin He,Chengbin Zhou,Tatiana Serdyuk,Jinjing Song,Ying Zhou,Shiqing Chen,Beimeng Yang,Shuangle Dong,Fujun Chen,Hechen Bao,Weidong Li,Xixia Chu,Lulu Song,Xiang Wang

doi:10.1186/s13041-017-0309-8

Lei Chen, Guang He + Show 16 more

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https://doi.org/10.1186/s13041-017-0309-8

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Journal: Molecular brain	Publication Date: Jul 3, 2017
Citations: 4	License type: open-access

Affiliation: Shanghai Jiao Tong University

Abstract

Studies have implied that the circadian oscillation of mitogen-activated protein kinase (MAPK) signal pathways is crucial for hippocampus-dependent memory. NF1 mouse models (Nf1 heterozygous null mutants; Nf1+/−) displayed enhanced MAPK activity in the hippocampus and resulted in memory deficits. We assumed a link between MAPK pathways and hippocampal rhythmic oscillations, which have never been explored in Nf1+/− mice. We demonstrated that the level of extracellular signal–regulated kinases 1 and 2 (ERK1/2) phosphorylation in Nf1+/− mice were significantly higher at nighttime than at daytime. Moreover, the in vivo recording revealed that for the Nf1+/− group, the power spectral density of theta rhythm significantly decreased and the firing rates of pyramidal neurons increased. Our results indicated that the hippocampal MAPK oscillation and theta rhythmic oscillations in Nf1+/− mice were disturbed and hinted about a possible mechanism for the brain dysfunction in Nf1+/− mice.

Highlights

Important transcriptional and translational events underlying long-term memory formation depend on the activation of mitogen-activated protein kinase (MAPK)signal pathways in the hippocampus [1,2,3]
Since hippocampal rhythmic oscillations play important role in sleep and cognitive function and theta rhythm is necessary for hippocampal dependent spatial learning
[30], to explore hippocampal theta rhythmic oscillations in Nf1+/− mice, we performed in vivo recording in CA1

Summary

Introduction

Important transcriptional and translational events underlying long-term memory formation depend on the activation of mitogen-activated protein kinase (MAPK)signal pathways in the hippocampus [1,2,3]. MAPK activity is the key pathophysiologic mechanism underlying neurofibromatosis type 1 (NF1) mutations in both mouse and humans [4]. NF1 is one of the most common single-gene causes of learning disabilities; studies on working memory and electrophysiology in NF1 mouse models (Nf1 heterozygous null mutants; Nf1+/−). Nf1 heterozygous null mutation results in enhanced ERK phosphorylation and increased gamma-aminobutyric acid (GABA) release in the hippocampus, which is reversed by the pharmacological downregulation of ERK. Past research has identified that lovastatin, a drug commonly used to treat hypercholesterolemia, could be a potent inhibitor of p21Ras/MAPK activity in the brain; in one study, lovastatin administration was found to decrease the levels of phosphorylated p44/42. Abnormal elevation in MAPK activity is central to the pathophysiology associated with NF1 mouse models [7]

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