Role of the Serine/Threonin Kinase Ndr2 in Integrin-mediated Neural Plasticity and Learning

• Applicants: Professor Alexander Dityatev, Ph.D.; Professor Dr. Oliver Stork
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 264761169

Integrin-mediated cell adhesion and signaling are critically involved in the development of the central nervous system and in neural plasticity in the adult. In particular, evidence suggests a role of beta1-integrins in hippocampal long-term potentiation and in hippocampus-dependent working memory tasks. However, the mechanisms that control the surface expression and activation of integrins in neuronal cells are still far from understood. We have recently identified the serine/threonine kinase Ndr2 as a regulator of beta1-integrin trafficking and its surface expression during neuronal differentiation. Ndr2, a target of the Hippo signaling pathway that is increased in expression upon stress, thereby controls dendritic growth and branching in hippocampal neurons. To further investigate the role of Ndr2/beta1-integrin interaction in vivo we have developed novel mutant mice that are constitutively or conditionally deficient in Ndr2. Our preliminary data suggest that Ndr2 also controls the dendritic branching of hippocampal pyramidal cells in vivo as well as working / short-term memory in hippocampus-dependent learning tasks. In this project we have teamed up to combine our expertise in behavioral genetics and molecular neurobiology (Stork) as well as cell- and systems physiology (Dityatev) for an in-depth analysis of the Ndr2/beta1-integrin interaction in structural and functional synaptic plasticity and memory formation. We will utilize state-of-the art technology, including laser microdissection and 2-photon microscopy, to determine molecular activation processes and synapse dynamics in relation to plasticity and memory formation. Thereby we will examine Ndr2 expression during hippocampal development and in response to stressors that lastingly alter the hippocampal circuitry. We will clarify the effect of Ndr2 ablation on beta1-integrin activation and beta1-integrin-dependent signaling in the hippocampus on a biochemical level and carefully examine the altered morphological and physiological properties of hippocampal neurons of Ndr2 deficient mice. This shall provide insight into the mechanisms of Ndr2/beta1-integrin action at hippocampal synapses and a framework for understanding their role in working memory in hippocampus-dependent tasks, which will be at the focus of our comprehensive behavioral analysis of the Ndr2 mutant mice. We further aim to dissect the role of Ndr2/beta1-integrin interaction in development and acute synaptic regulation. To this end we will employ our novel conditional Ndr2 mutants and different CRE recombinase driver lines targeting hippocampal principle cells during postnatal development and adulthood. Along the same line, we will investigate the relevance of Ndr2-dependent cellular processes for the debilitating effects of stress exposure in juvenility and adulthood and will examine the potential recovery of synaptic plasticity and learning in Ndr2 deficient mice through acute integrin stimulation.

• DFG Programme: Research Grants