The Serine/Threonine Kinase NDR2 Regulates Integrin Signaling, Synapse Formation, and Synaptic Plasticity in the...

Nuclear Dbf2-related (NDR) kinases are core components of the Hippo pathway, which controls neuronal polarity and neurite growth in the central nervous system (CNS). NDR2 is the principal NDR kinase in the mouse CNS, where it has been shown to regulate integrin-dependent dendritic branching as well as growth and plasticity in hippocampal mossy fibers. Given the well-established involvement of integrins in plasticity, we hypothesized that NDR2 might regulate synapse formation and plasticity through integrin-mediated mechanisms. In this study, using constitutive NDR2 null mutant mice, we demonstrate that Ndr2 deficiency leads to a reduction of T788/789 phosphorylated β1 integrin expression at synaptic sites both in the hippocampal area CA1 and in primary hippocampal neurons in vitro. This reduction is associated with decreased synaptic density in both conditions and accompanied by reduced long-term potentiation in the synapses between Schaffer collaterals/commissural fibers and CA1 pyramidal cells, which could be restored by activation of integrins with an arginine-glycine-aspartate-containing peptide, as well as with mild spatial memory deficits. Together, our results suggest that NDR2 is involved in integrin-dependent synapse formation and plasticity in the mouse hippocampus.