Research Report 2010 - MDC

paired-pulse facilitation, less depression during prolongedrepetitive activation and a lower rate of spontaneouspostsynaptic currents that are based on a lowerrelease probability of neurotransmitters at early butinterestingly not at mature postnatal stages.CALEB is a transmembrane protein composed of an N-terminal segment that contains chondroitinsulfatechains followed by an acidic stretch, and an EGF-likedomain, a transmembrane and a cytoplasmic segment.The EGF-like domain of CALEB is related to the EGFdomains of the neuregulins, TGFα or EGF itself andtherefore CALEB might be considered to be a memberof the EGF-family of differentiation factors. CALEBappears to be generated as a precursor protein thatbecomes converted in a truncated transmembraneform with an exposed EGF domain. In slices and in culturesthis conversion occurs at the cell surface which isfacilitated by membrane depolarization and calciuminflux through voltage gated calcium channels.The understanding of the cell biological function ofCALEB in the development of neuronal circuits is ofgreat interest since genetic linkage studies identifiedCALEB as a putative susceptibility gene for schizophreniain humans which is considered as a disorder ofdevelopment.Figure 3. Localization of CALEB on dendrites.CALEB (green) is primarily found on structures that are positive forMAP2 – a marker for dendrites – and appears to be absent fromaxons which are stained by anti-neurofilament (red).Neural cell adhesion proteins and their functionin the formation of neural networksCell adhesion proteins of the Ig superfamily, the cadherinsor the neurexins are thought be essential for theformation of neuronal circuits. Currently we are characterizingthe Ig superfamily member CAR (coxsackieadenovirusreceptor) that is strongly expressed atdevelopmental stages and then becomes down regulatedin the mature brain. CAR is a transmembrane proteincomposed of two Ig-like domains and an intracellularsegment that becomes alternatively spliced. Ourelectrophysiological recordings and calcium imagingmeasurements using wildtype and knockout neuronsreveal that CAR is not simply an adhesion protein. Incontrast, manipulation of CAR by using a specific ligandindicates that CAR affects intracellular calcium signalingand thereby influences the development of neuronalnetworks. Binding as well as structural studiesdemonstrate homophilic and heterophilic interactionsof CAR for which specific extracellular domains areimportant.160 Function and Dysfunction of the Nervous System