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Publication : Evidence for opposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation.

First Author  Thakar S Year  2017
Journal  Proc Natl Acad Sci U S A Volume  114
Issue  4 Pages  E610-E618
PubMed ID  28057866 Mgi Jnum  J:239529
Mgi Id  MGI:5829122 Doi  10.1073/pnas.1612062114
Citation  Thakar S, et al. (2017) Evidence for opposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation. Proc Natl Acad Sci U S A 114(4):E610-E618
abstractText  The signaling mechanisms that choreograph the assembly of the highly asymmetric pre- and postsynaptic structures are still poorly defined. Using synaptosome fractionation, immunostaining, and coimmunoprecipitation, we found that Celsr3 and Vangl2, core components of the planar cell polarity (PCP) pathway, are localized at developing glutamatergic synapses and interact with key synaptic proteins. Pyramidal neurons from the hippocampus of Celsr3 knockout mice exhibit loss of approximately 50% of glutamatergic synapses, but not inhibitory synapses, in culture. Wnts are known regulators of synapse formation, and our data reveal that Wnt5a inhibits glutamatergic synapses formed via Celsr3. To avoid affecting earlier developmental processes, such as axon guidance, we conditionally knocked out Celsr3 in the hippocampus 1 week after birth. The CA1 neurons that lost Celsr3 also showed a loss of approximately 50% of glutamatergic synapses in vivo without affecting the inhibitory synapses assessed by miniature excitatory postsynaptic current (mEPSC) and electron microscopy. These animals displayed deficits in hippocampus-dependent behaviors in adulthood, including spatial learning and memory and fear conditioning. In contrast to Celsr3 conditional knockouts, we found that the conditional knockout of Vangl2 in the hippocampus 1 week after birth led to a large increase in synaptic density, as evaluated by mEPSC frequency and spine density. PCP signaling is mediated by multiple core components with antagonizing functions. Our results document the opposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation.
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