Neuritin Enhances Synaptic Transmission in Medial Prefrontal Cortex in Mice by Increasing CaV3.3 Surface Expression.

Jun-Mei Lu,Chen Ling,Zhao-Yang Li,Yan-Ai Mei,Dong-Dong Liu

doi:10.1093/cercor/bhx082

Abstract

Neuritin is a neurotrophic factor involved in neural development and synaptic plasticity. However, its role in modulating synaptic transmission remains unclear. Here, we investigated the effects of neuritin on miniature excitatory postsynaptic currents (mEPSCs) and glutamate release in the medial prefrontal cortex (mPFC) in mice. Incubation of mPFC slices with neuritin for 45 min significantly increased mEPSC frequency and glutamate release as measured by high-performance liquid chromatography, which was mimicked by insulin and abrogated by an insulin receptor (IR) inhibitor. Neuritin-induced upregulation of synaptic transmission was correlated with activation of ERK, and inhibition of mitogen-activated protein kinases/extracellular signal-regulated kinases (MEK/ERK) activity attenuated the neuritin-induced increase in mEPSC frequency and glutamate release. T-type calcium channel inhibitors but not the L-type inhibitor abolished the inward calcium current and the effects of neuritin on mEPSC frequency and glutamate release. Western blotting of membrane proteins showed that neuritin promoted surface expression of CaV3.3 α-subunit, which was also eliminated by inhibition of IR or MEK/ERK activity. The effects of neuritin on mEPSC frequency, glutamate release, and CaV3.3 α-subunit expression were inhibited by an intracellular protein-transport inhibitor. These results confirm involvement of the IR and ERK signaling pathway, and provide novel insights into the mechanisms of neuritin function in synaptic transmission.

Highlights

Neuritin, known as candidate plasticity gene 15 (CPG15), was originally isolated during screening for genes induced by kainate-stimulated seizures in rat dentate gyrus and in humans (Nedivi et al 1993; Naeve et al 1997)
Data from 241 neurons showed that incubation with neuritin 50 ng/mL for 45 min increased miniature excitatory postsynaptic currents (mEPSCs) frequency by 9.63% compared to the control group
MEPSC frequency was unaffected by incubation with neuritin 150 ng/mL for 10 min compared with the control group

Summary

Introduction

Known as candidate plasticity gene 15 (CPG15), was originally isolated during screening for genes induced by kainate-stimulated seizures in rat dentate gyrus and in humans (Nedivi et al 1993; Naeve et al 1997). Highly conserved protein attached to the cell membrane via a glycosylphosphatidylinositol anchor (Nedivi et al 1993). It has been shown to exert non–cell-autonomous functions by binding to receptors (Nedivi et al 1998; Cantallops et al 2000), no specific neuritin receptor has yet been identified. We recently reported that neuritin upregulated the expression of IA channel Kv4.2 subunits in rat cerebellum granule cells (CGNs) via insulin receptor (IR)-activated mitogen-activated protein kinases/extracellular signal-regulated kinases (MEK/ERK) and Akt/mammalian target of rapamycin (mTOR) signaling pathways (Yao et al 2012). Whether the same receptors and signaling pathways occur in other neurons remains to be determined

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Conclusion