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As the catalytic component of γ-secretase, presenilin (PS) has long been studied in the context of Alzheimer's disease through cleaving the amyloid precursor protein. PS/γ-secretase, however, also cleaves a multitude of single-pass transmembrane proteins that are important during development, including Notch, the netrin receptor DCC, cadherins, drebrin-A, and the EphB2 receptor. Because transgenic PS-KO mice do not survive to birth, studies of this molecule during later embryonic or early postnatal stages of development have been carried out using cell cultures or conditional knock-out mice, respectively. As a result, the function of PS in synapse formation had not been well-addressed. Here, we study the role of PS in the developing Xenopus tadpole retinotectal circuit, an in-vivo model that allows for protein expression to be manipulated specifically during the peak of synapse formation between retinal ganglion cells and tectal neurons. We found that inhibiting PS in the postsynaptic tectal neurons impaired tadpole visual avoidance behavior. Whole cell recordings indicated weaker retinotectal synaptic transmission which was characterized by significant reductions in both NMDA receptor (NMDAR)- and AMPA receptor (AMPAR)-mediated currents. We also found that expression of the C-tail fragment of the EphB2 receptor, which is normally cleaved by PS/γ-secretase and which has been shown to upregulate NMDARs at the synapse, rescued the reduced NMDAR-mediated responses. Our data determine that normal PS function is important for proper formation and strengthening of retinotectal synapses through cleaving the EphB2 receptor.
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