An in vivo mouse model of long-term potentiation at synapses between primary afferent C-fibers and spinal dorsal horn neurons: essential role of EphB1 receptor.
BACKGROUND
Long-term potentiation (LTP), a much studied cellular model of synaptic plasticity, has not been demonstrated at synapses between primary afferent C-fibers and spinal dorsal horn (DH) neurons in mice in vivo. EphrinB-EphB receptor signaling plays important roles in synaptic connection and plasticity in the nervous system, but its role in spinal synaptic plasticity remains unclear.


RESULTS
This study characterizes properties of LTP at synapses of C-fibers onto neurons in the superficial DH following high-frequency stimulation (HFS) of a peripheral nerve at an intensity that activates C-fibers and examines associated activation of Ca2+/calmodulin-activated protein kinase II (p-CaMKII), extracellular signal-regulated kinase (p-ERK) and the cyclic AMP response element binding protein (p-CREB) and expression of c-Fos, and it investigates further roles for the EphB1 receptor in LTP. HFS induced LTP within 5 min and lasts for 3-8 h during the period of recording and resulted in upregulation of p-CaMKII, p-ERK and p-CREB protein levels in the spinal cord and expression of c-Fos in DH. Intrathecal pretreatment of MK-801 or EphB2-Fc prevented LTP and significantly reduced upregulation of p-CaMKII, p-ERK, p-CREB and c-Fos. Further, targeted mutation of EphB1 receptor prevented induction of LTP and associated increases in phosphorylation of CaMKII, ERK, and CREB.


CONCLUSIONS
This study provides an in vivo mouse model of LTP at synapses of C-fibers onto the superficial DH neurons that will be valuable for studying the DH neuron excitability and their synaptic plasticity and hyperalgesia. It further takes advantage of examining functional implications of a specific gene targeted mice and demonstrates that the EphB1 receptor is essential for development of LTP.
Liu
Wen-Tao
WT
Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, Jiangsu, PR China. wliu@parkercc.edu
Han
Yuan
Y
Li
Hao-Chuan
HC
Adams
Brandt
B
Zheng
Ji-Hong
JH
Wu
Yong-Ping
YP
Henkemeyer
Mark
M
Song
Xue-Jun
XJ
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics; D017774:Long-Term Potentiation; D051379:Mice; D023421:Models, Animal; D036421:Nerve Fibers, Unmyelinated / Q000502:physiology*; D010525:Peripheral Nerves / Q000502:physiology; D020671:Posterior Horn Cells / Q000502:physiology*; D036225:Receptor, EphB1 / Q000502:physiology*; D013116:Spinal Cord / Q000378:metabolism; D013569:Synapses / Q000502:physiology*; D004561:Transcutaneous Electric Nerve Stimulation; D015854:Up-Regulation
D017362:Cyclic AMP Response Element-Binding Protein; D036225:Receptor, EphB1; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D048049:Extracellular Signal-Regulated MAP Kinases