EphA4 Regulates Hippocampal Neural Precursor Proliferation in the Adult Mouse Brain by d-Serine Modulation of N-Methyl-d-Aspartate Receptor Signaling

Abstract

The hippocampal dentate gyrus (DG) is a major region of the adult rodent brain in which neurogenesis occurs throughout life. The EphA4 receptor, which regulates neurogenesis and boundary formation in the developing brain, is also expressed in the adult DG, but whether it regulates adult hippocampal neurogenesis is not known. Here, we show that, in the adult mouse brain, EphA4 inhibits hippocampal precursor cell proliferation but does not affect precursor differentiation or survival. Genetic deletion or pharmacological inhibition of EphA4 significantly increased hippocampal precursor proliferation in vivo and in vitro, by blocking EphA4 forward signaling. EphA4 was expressed by mature hippocampal DG neurons but not neural precursor cells, and an EphA4 antagonist, EphA4-Fc, did not activate clonal cultures of precursors until they were co-cultured with non-precursor cells, indicating an indirect effect of EphA4 on the regulation of precursor activity. Supplementation with d-serine blocked the increased precursor proliferation induced by EphA4 inhibition, whereas blocking the interaction between d-serine and N-methyl-d-aspartate receptors (NMDARs) promoted precursor activity, even at the clonal level. Collectively, these findings demonstrate that EphA4 indirectly regulates adult hippocampal precursor proliferation and thus plays a role in neurogenesis via d-serine-regulated NMDAR signaling.

Role of EphA4 in Mediating Motor Neuron Death in MND

“…However, further investigation is required to address how EphA4 regulates the D-serine levels in the brain in vivo, and which source of D-serine (astrocytes and/or neurons) has been affected. This EphA4-regulated D-serine concentration has already been observed during adult hippocampal neurogenesis in vivo and in vitro [71]. We have shown that either pharmacological EphA4 inhibition by EphA4-Fc or genetic deletion of EphA4 upregulates adult hippocampal neural precursor proliferation.…”

“…Moreover, this increased precursor activity induced by the inhibition of EphA4 could be rescued by exogenous D-serine supplementation. In addition, a specific blockage of the interaction between D-serine and NMDARs promoted precursor proliferation directly [71]. These results suggest that EphA4 inhibition indirectly leads to an increase in adult precursor proliferation, by decreasing the level of D-serine, thus inducing downregulation of NMDARs, which directly exerted positive effects on precursor proliferation.…”

The Interaction of EphA4 With PDGFRβ Regulates Proliferation and Neuronal Differentiation of Neural Progenitor Cells in vitro and Promotes Neurogenesis in vivo

“…The activity of EphA4 was reported to promote neurodegeneration in several models. EphA4 activation mediates synaptic damage in AD (Vargas et al, 2014;Zhao et al, 2018) and its inhibition rescues neurodegeneration in amyotrophic lateral sclerosis (ALS; Faruqi, 2012;Van Hoecke et al, 2012). EphA4 regulates proliferation of neural stem cells during cortical neurogenesis of the developing and the postnatal brain (North et al, 2009;Khodosevich et al, 2011).…”

Possible role of EphA4 and VEGFR2 interactions in neural stem and progenitor cell differentiation

“…EphA4/ephrin-A signaling serves an important role in establishing the brain vascular system which supports the adult neurogenic niche (30). EphA4 regulates hippocampal neurogenesis via d-serine-regulated N-Methyl-D-aspartic acid receptor signaling in the adult mouse brain (31). As a major angiogenic factor, VEGF promotes neurogenesis in NSPCs in vitro and in the adult brain through the VEGFR2 signaling pathway (13).…”