Amygdala EphB2 Signaling Regulates Glutamatergic Neuron Maturation and Innate Fear.
The amygdala serves as emotional center to mediate innate fear behaviors that are reflected through neuronal responses to environmental aversive cues. However, the molecular mechanism underlying the initial neuron responses is poorly understood. In this study, we monitored the innate defensive responses to aversive stimuli of either elevated plus maze or predator odor in juvenile mice and found that glutamatergic neurons were activated in amygdala. Loss of EphB2, a receptor tyrosine kinase expressed in amygdala neurons, suppressed the reactions and led to defects in spine morphogenesis and fear behaviors. We further found a coupling of spinogenesis with these threat cues induced neuron activation in developing amygdala that was controlled by EphB2. A constitutively active form of EphB2 was sufficient to rescue the behavioral and morphological defects caused by ablation of ephrin-B3, a brain-enriched ligand to EphB2. These data suggest that kinase-dependent EphB2 intracellular signaling plays a major role for innate fear responses during the critical developing period, in which spinogenesis in amygdala glutamatergic neurons was involved.



Generation of innate fear responses to threat as an evolutionally conserved brain feature relies on development of functional neural circuit in amygdala, but the molecular mechanism remains largely unknown. We here identify that EphB2 receptor tyrosine kinase, which is specifically expressed in glutamatergic neurons, is required for the innate fear responses in the neonatal brain. We further reveal that EphB2 mediates coordination of spinogenesis and neuron activation in amygdala during the critical period for the innate fear. EphB2 catalytic activity plays a major role for the behavior upon EphB-ephrin-B3 binding and transnucleus neuronal connections. Our work thus indicates an essential synaptic molecular signaling within amygdala that controls synapse development and helps bring about innate fear emotions in the postnatal developing brain.
Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China, Neuroscience Division, Department of Anatomy, Histology and Embryology.
Xiao-Na
XN
Zhu
Neuroscience Division, Department of Anatomy, Histology and Embryology, Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, and Shanghai Key Laboratory of Reproductive Medicine, Shanghai 200025, China.
Xian-Dong
XD
Liu
Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China, The Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China, and.
Hanyi
H
Zhuang
Departments of Neuroscience and Developmental Biology, Kent Waldrep Center for Basic Research on Nerve Growth and Regeneration, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
Mark
M
Henkemeyer
Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China, xunanjie@sjtu.edu.cn jingyuyang2006@gmail.com.
Jing-Yu
JY
Yang
Neuroscience Division, Department of Anatomy, Histology and Embryology, Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, and Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China, Shanghai Key Laboratory of Reproductive Medicine, Shanghai 200025, China, xunanjie@sjtu.edu.cn jingyuyang2006@gmail.com.
Nan-Jie
0000-0003-2147-3352
NJ
Xu
D000375:Aging / Q000502:physiology; D000679:Amygdala / Q000502:physiology*; D000818:Animals; D003674:Defense Mechanisms; D005239:Fear / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D005971:Glutamates / Q000378:metabolism*; D007323:Instinct; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D036183:Receptor, EphB2 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D005971:Glutamates; C586311:Ephb2 protein, mouse; D036183:Receptor, EphB2
EphB2; amygdala; ephrin-B3; glutamatergic neuron; innate fear; spine
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