Ephrin-A5 and EphA5 interaction induces synaptogenesis during early hippocampal development.
BACKGROUND
Synaptogenesis is a fundamental step in neuronal development. For spiny glutamatergic synapses in hippocampus and cortex, synaptogenesis involves adhesion of pre and postsynaptic membranes, delivery and anchorage of pre and postsynaptic structures including scaffolds such as PSD-95 and NMDA and AMPA receptors, which are glutamate-gated ion channels, as well as the morphological maturation of spines. Although electrical activity-dependent mechanisms are established regulators of these processes, the mechanisms that function during early development, prior to the onset of electrical activity, are unclear. The Eph receptors and ephrins provide cell contact-dependent pathways that regulate axonal and dendritic development. Members of the ephrin-A family are glycosyl-phosphatidylinositol-anchored to the cell surface and activate EphA receptors, which are receptor tyrosine kinases.


RESULTS
Here we show that ephrin-A5 interaction with the EphA5 receptor following neuron-neuron contact during early development of hippocampus induces a complex program of synaptogenic events, including expression of functional synaptic NMDA receptor-PSD-95 complexes plus morphological spine maturation and the emergence of electrical activity. The program depends upon voltage-sensitive calcium channel Ca2+ fluxes that activate PKA, CaMKII and PI3 kinase, leading to CREB phosphorylation and a synaptogenic program of gene expression. AMPA receptor subunits, their scaffolds and electrical activity are not induced. Strikingly, in contrast to wild type, stimulation of hippocampal slices from P6 EphA5 receptor functional knockout mice yielded no NMDA receptor currents.


CONCLUSIONS
These studies suggest that ephrin-A5 and EphA5 signals play a necessary, activity-independent role in the initiation of the early phases of synaptogenesis. The coordinated expression of the NMDAR and PSD-95 induced by eprhin-A5 interaction with EphA5 receptors may be the developmental switch that induces expression of AMPAR and their interacting proteins and the transition to activity-dependent synaptic regulation.
Akaneya
Yukio
Y
Department of Biochemistry, New York University School of Medicine, New York, New York, United States of America.
Sohya
Kazuhiro
K
Kitamura
Akihiko
A
Kimura
Fumitaka
F
Washburn
Chris
C
Zhou
Renping
R
Ninan
Ipe
I
Tsumoto
Tadaharu
T
Ziff
Edward B
EB
D000818:Animals; D015220:Calcium Channels / Q000378:metabolism; D002450:Cell Communication; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D036386:Ephrin-A5 / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D055786:Gene Knockout Techniques; D006624:Hippocampus / Q000166:cytology* / Q000254:growth & development* / Q000378:metabolism; D006801:Humans; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011485:Protein Binding; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D036123:Receptor, EphA5 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction; D013131:Spine / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission; D013997:Time Factors; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
D015220:Calcium Channels; D017362:Cyclic AMP Response Element-Binding Protein; D036386:Ephrin-A5; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; D000242:Cyclic AMP; D019869:Phosphatidylinositol 3-Kinases; D036123:Receptor, EphA5; D017868:Cyclic AMP-Dependent Protein Kinases; D020764:cdc42 GTP-Binding Protein
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