NGPF2 triggers synaptic scaling up through ALK-LIMK-cofilin-mediated mechanisms

Zikai Zhou; Guiqin He; Xiaoyun Zhang; Xin Lv; Xiaolin Zhang; An Liu; Shuting Xia; Hao Xie; Rui Dang; Lifang Han; Junxia Qi; Yanghong Meng; Shunying Yu; Wei Xie; Zhengping Jia

doi:10.1016/j.celrep.2021.109515

NGPF2 triggers synaptic scaling up through ALK-LIMK-cofilin-mediated mechanisms

Cell Rep. 2021 Aug 17;36(7):109515. doi: 10.1016/j.celrep.2021.109515.

Authors

Zikai Zhou¹, Guiqin He², Xiaoyun Zhang³, Xin Lv⁴, Xiaolin Zhang⁴, An Liu⁵, Shuting Xia⁶, Hao Xie⁵, Rui Dang⁵, Lifang Han⁵, Junxia Qi⁵, Yanghong Meng⁷, Shunying Yu⁴, Wei Xie⁵, Zhengping Jia⁸

Affiliations

¹ Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; School of Life Science and Technology, Southeast University, 2 Sipailou Road, Nanjing 210096, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Zhongshan Institute for Drug Discovery, the Institutes of Drug Discovery and Development, Chinese Academy of Sciences, Zhongshan, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China. Electronic address: zhouzikai@simm.ac.cn.
² Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; School of Life Science and Technology, Southeast University, 2 Sipailou Road, Nanjing 210096, China.
³ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Zhongshan Institute for Drug Discovery, the Institutes of Drug Discovery and Development, Chinese Academy of Sciences, Zhongshan, China.
⁴ Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁵ School of Life Science and Technology, Southeast University, 2 Sipailou Road, Nanjing 210096, China.
⁶ School of Life Science and Technology, Southeast University, 2 Sipailou Road, Nanjing 210096, China; Neurosciences & Mental Health, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
⁷ Neurosciences & Mental Health, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
⁸ Neurosciences & Mental Health, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada. Electronic address: zhengping.jia@sickkids.ca.

PMID: 34407403
DOI: 10.1016/j.celrep.2021.109515

Abstract

Synaptic scaling is an extensively studied form of homeostatic plasticity critically involved in various brain functions. Although it is accepted that synaptic scaling is expressed through the postsynaptic accumulation of AMPA receptors (AMPARs), the induction mechanism remains elusive. In this study, we show that TTX treatment induces rapid but transient release of the neurite growth-promoting factor 2 (NGPF2), and this release is necessary and sufficient for TTX-induced scaling up. In addition, we show that inhibition of the anaplastic lymphoma kinase (ALK)-LIMK-cofilin signaling pathway blocks TTX- and NGPF2-induced synaptic scaling up. Furthermore, we show that TTX-induced release of NGPF2 is protein synthesis dependent and requires fragile X mental retardation protein 1 (FMRP1). These results indicate that activity blockade induces NGPF2 synthesis and release to trigger synaptic scaling up through LIMK-cofilin-dependent actin reorganization, spine enlargement, and stabilization of AMPARs at the synapse.

Keywords: AMPA receptor; LIM-kinase; anaplastic lymphoma kinase; cofilin; fragile X mental retardation protein 1; neurite growth promoting factor 2; synaptic scaling up.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Actin Depolymerizing Factors / metabolism
Anaplastic Lymphoma Kinase
Animals
CHO Cells
Cricetulus
Dendritic Spines / drug effects
Dendritic Spines / metabolism
Excitatory Postsynaptic Potentials / drug effects
Fragile X Mental Retardation Protein / metabolism
Lim Kinases / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Nerve Tissue Proteins* / metabolism
Protein Biosynthesis
Receptors, AMPA / metabolism
Signal Transduction
Synapses / drug effects
Synapses / metabolism
Tetrodotoxin / pharmacology

Substances

Actin Depolymerizing Factors
Anaplastic Lymphoma Kinase
Fragile X Mental Retardation Protein
Lim Kinases
Limk1 protein, mouse
Nerve Tissue Proteins
Receptors, AMPA
Tetrodotoxin
Mdk protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding