期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：15
页码：4797-4802
DOI：10.1073/pnas.1417053112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceNMDA receptors (NMDARs) are key components of excitatory synapses. Here we report that Wnt signaling via activation of tyrosine kinase-like orphan receptor 2 can regulate synaptic NMDARs. Understanding what controls number and subunit composition is central to understand neuropathologies associated with dysfunction of synaptic NMDARs, including Alzheimer's disease and schizophrenia. Our data indicate a previously unidentified role for Wnt signaling in the regulation of established synaptic connections and provides a mechanism for Wnt ligands to modulate basal synaptic transmission, synaptic plasticity, and brain functions acutely. Wnt signaling has a well-established role as a regulator of nervous system development, but its role in the maintenance and regulation of established synapses in the mature brain remains poorly understood. At excitatory glutamatergic synapses, NMDA receptors (NMDARs) have a fundamental role in synaptogenesis, synaptic plasticity, and learning and memory; however, it is not known what controls their number and subunit composition. Here we show that the receptor tyrosine kinase-like orphan receptor 2 (RoR2) functions as a Wnt receptor required to maintain basal NMDAR-mediated synaptic transmission. In addition, RoR2 activation by a noncanonical Wnt ligand activates PKC and JNK and acutely enhances NMDAR synaptic responses. Regulation of a key component of glutamatergic synapses through RoR2 provides a mechanism for Wnt signaling to modulate synaptic transmission, synaptic plasticity, and brain function acutely beyond embryonic development.
