Aktivitäts-abhängige Regulation von neuralen Zelloberflächenproteinen und ihre Funktion bei der Synaptogenese: Funktionelle Charakterisierung von CALEB

• Applicant: Professor Dr. Fritz G. Rathjen
• Subject Area: Developmental Neurobiology
• Term: from 2007 to 2011
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 46813617

Neuronal activity is essential for the complex wiring of the brain. The links between electric activity and molecules that contribute to structural remodeling of neuronal circuits are not well understood. In past years we have therefore screened for cell surface proteins which establish a link between electric activity and which might play a role in circuit formation. We characterized two cell surface proteins: CAR (coxsackievirus adenovirus receptor) and CALEB. CAR is a cell adhesion protein of the Ig superfamily which modulates the frequency of action potentials and regulates the level of intracellular free calcium. It is primarily expressed in the developing nervous system and is almost undetectable in the mature nervous system. CALEB is a chondroitinsulfate-containing member of the EGF-family of differentiation factors that becomes proteolytically converted at the plasma membrane. This conversion is facilitated by electric activity. Its absence results in deficits of presynaptic differentiation in several brain structures at early developmental stages and in impairments in the elimination process of the climbing fiber synapse on Purkinje cells. CALEB is restricted to the central nervous system and is predominantly expressed in the somato-dendritic compartment. Aims of this follow-up application are investigations on these two proteins and two additional proteins of the Ig superfamily structurally related to CAR (termed BT-IgSF and clmp). On the basis of their structural similarity we assume that clmp and BT-IgSF subserve a similar function as CAR. For CAR and BT-IgSF we have generated transgenic mouse models and for clmp we are in the process in establishing a knockout. We intend to study the development of neuronal circuits in these mutant mice. By electrophysiological and histological tracing techniques we ask whether the formation of neuronal circuits is impaired in these mutant mice. Furthermore, we intend to characterize a signaling cascade implicated in the CAR-mediated release of calcium from intracellular stores. The same will be done for BT-IgSF and clmp. We speculate that CAR, BT-IgSF and clmp modulate the level of intracellular free calcium in neighboring neurons and thereby influence calcium waves in neural tissues. To characterize the role of CALEB in the process of presynaptic differentiation further we will screen for a pre-synaptic receptor protein of CALEB. In addition several electrophysiological characterizations in different brain structures in CALEB mutant mice as wells as investigations on the signaling function of CALEB are planned.

• DFG Programme: Research Grants