Abstract
Vascular endothelial growth factor (VEGF) is an angiogenic factor that play important roles in the nervous system, although it is still unclear which receptors transduce those signals in neurons. Here, we show that in the developing hippocampus VEGFR2 (also known as KDR or FLK1) is expressed specifically in the CA3 region and it is required for dendritic arborization and spine morphogenesis in hippocampal neurons. Mice lacking VEGFR2 in neurons (Nes-cre Kdrlox/-) show decreased dendritic arbors and spines as well as a reduction in long-term potentiation (LTP) at the associational-commissural - CA3 synapses. Mechanistically, VEGFR2 internalization is required for VEGF-induced spine maturation. In analogy to endothelial cells, ephrinB2 controls VEGFR2 internalization in neurons. VEGFR2-ephrinB2 compound mice (Nes-cre Kdrlox/+ Efnb2lox/+) show reduced dendritic branching, reduced spine head size and impaired LTP. Our results demonstrate the functional crosstalk of VEGFR2 and ephrinB2 in vivo to control dendritic arborization, spine morphogenesis and hippocampal circuitry development.
Highlights
During development, the hippocampus undergoes typical stages of neuronal development involving proliferation, differentiation, synapse and circuit formation, and the maturation of synaptic connections
In order to address the role of VEGFR2 in the developing hippocampus, we started by looking at the expression patterns of VEGFR2 in the different populations of hippocampal neurons
Immunohistochemistry in the developing hippocampus at postnatal day 10 (P10) showed, as expected, high expression of VEGFR2 in the vessels, but interestingly in CA3 pyramidal neurons (Figure 1A,B). This expression pattern was confirmed by using a knock-in mouse expressing VEGFR2-GFP, where exon 1 of the Kdr gene is replaced by GFP (Ema et al, 2006), and GFP labeling reflects VEGFR2 endogenous expression (Figure 1—figure supplement 1A)
Summary
The hippocampus undergoes typical stages of neuronal development involving proliferation, differentiation, synapse and circuit formation, and the maturation of synaptic connections. During late neonatal and early postnatal brain development, dendritic arbors are highly dynamic and undergo continuous changes in shape and orientation (Dailey and Smith, 1996). Neurons extend and retract branches as they mature and only a subset of the original dendrites become stabilized in the mature brain. Such an early dynamic period is essential for proper wiring, synapse formation and the establishment of neural circuits (Wong and Wong, 2000; Matsuzaki et al, 2001; Koleske, 2013) During this time, dendrite stabilization and synapse formation are strongly coupled. As circuits mature further in juvenile stages, structural plasticity decreases and dendrites become stabilized, whereas dendritic spines stay dynamic and change in shape
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