Regulation of hippocampal synaptic plasticity by the tyrosine kinase receptor, REK7/EphA5, and its ligand, AL-1/Ephrin-A5.
The Eph-related tyrosine kinase receptor, REK7/EphA5, mediates the effects of AL-1/Ephrin-A5 and related ligands and is involved in the guidance of retinal, cortical, and hippocampal axons during development. The continued expression of REK7/EphA5 in the adult brain, in particular in areas associated with a high degree of synaptic plasticity such as the hippocampus, raises the question of its function in the mature nervous system. In this report we examined the role of REK7/EphA5 in synaptic remodeling by asking if agents that either block or activate REK7/EphA5 affect synaptic strength in hippocampal slices from adult mouse brain. We show that a REK7/EphA5 antagonist, soluble REK7/EphA5-IgG, impairs the induction of long-term potentiation (LTP) without affecting other synaptic parameters such as normal synaptic transmission or paired-pulse facilitation. In contrast, perfusion with AL-1/Ephrin-A5-IgG, an activator of REK7/EphA5, induces a sustained increase in normal synaptic transmission that partially mimics LTP. The sustained elevation of normal synaptic transmission could be attributable to a long-lasting binding of the AL-1/Ephrin-A5-IgG to the endogenous REK7/EphA5 receptor, as revealed by immunohistochemistry. Furthermore, maximal electrical induction of LTP occludes the potentiating effects of subsequent treatment with AL-1/Ephrin-A5-IgG. Taken together these results implicate REK7/EphA5 in the regulation of synaptic plasticity in the mature hippocampus and suggest that REK7/EphA5 activation is recruited in the LTP induced by tetanization.
Department of Neuroscience, Genentech, Inc., MS 72, 1 DNA Way, South San Francisco, California, 94080, USA. gao@gene.com
W Q
WQ
Gao
N
N
Shinsky
M P
MP
Armanini
P
P
Moran
J L
JL
Zheng
J L
JL
Mendoza-Ramirez
H S
HS
Phillips
J W
JW
Winslow
I W
IW
Caras
D000818:Animals; D001369:Axons / Q000737:chemistry / Q000187:drug effects; D015704:CD4 Antigens / Q000494:pharmacology; D002478:Cells, Cultured; D003712:Dendrites / Q000737:chemistry / Q000187:drug effects; D018891:Dentate Gyrus / Q000737:chemistry* / Q000201:enzymology*; D004558:Electric Stimulation; D036383:Ephrin-A2; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005455:Fluorescent Antibody Technique; D015971:Gene Expression Regulation, Enzymologic; D007074:Immunoglobulin G / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008568:Memory / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis / Q000235:genetics* / Q000494:pharmacology; D036123:Receptor, EphA5; D012995:Solubility; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics* / Q000494:pharmacology
D015704:CD4 Antigens; D036383:Ephrin-A2; D007074:Immunoglobulin G; D012333:RNA, Messenger; D014157:Transcription Factors; D020794:Receptor Protein-Tyrosine Kinases; D036123:Receptor, EphA5