Impaired Synapse Function during Postnatal Development in the Absence of CALEB, an EGF-like Protein Processed by Neuronal Activity

CALEB was characterized to be an activity-dependent processed cell-surface protein, which affects presynaptic properties at early developmental stages. (A) CALEB is expressed as plasma membrane polypeptide (in chick retina as a 140 kD form) that is processed by depolarisation with KCl or activation of glutamate receptors resulting in a transmembrane form composed of the EGF domain, the transmembrane region and the cytoplasmic segment. A prominent intermediate form in the chick retina is the 80 kD component that is further transformed. AB - acidic box, LP - leucine-proline rich region, PM - plasma membrane. (B) CALEB deficiency in a knockout mouse model results in a reduced release probability of the neurotransmitter at early developmental stages. In paired-pulse experiments, a form of short-term synaptic plasticity, in acute brain slices of the colliculus superior the CALEB deficient synapses show higher paired-pulse facilitation than wild-type synapses (interstimulus interval 20 ms and 100 ms). P3 - postnatal day 3. (Figure reproduced from Neuron 46,(2), 21 April 2005, p. 233-245, Cell Press, Copyright 2005 Elsevier Inc. All rights reserved.)

While humans are born with a complete set of nerve cells, the main development of the connectivity between neurons, namely the building of synapses, occurs primarily post-natally, which might be modulated by sensory experience. Despite the recent knowledge in understanding the function of synapses, the molecular components of synapse development remain largely unknown.

Fritz Rathjen and colleagues have been interested in identifying cell surface proteins regulated by neuronal activity and studying their expression and function during periods of active synaptogenesis. Such proteins are thought to be candidates in the establishment and regulation of synapses and synaptic plasticity. In 1997, the team discovered CALEB, a transmembrane protein of the epidermal growth factor (EGF) family. Now, René Jüttner (laboratory of Fritz Rathjen) and colleagues have characterized the role of CALEB in synapse development.

Using CALEB-deficient mice, they observed changes in the synaptic transmission; namely, in the absence of CALEB, the synapses displayed higher paired-pulse ratios, less depression during prolonged repetitive activation, a lower rate of spontaneous postsynaptic currents, and a lower release probability at early, but not mature, postnatal stages, while the number and morphological characteristics of the synapses remained unchanged. Thus, the inactivation of the CALEB gene apparently alters the release features of synapses during the early phase of synapse development. The fact that adult CALEB-deficient mice lack a phenotype suggests that other mechanisms are able to compensate for the missing protein in these mice and/or that CALEB is only critical during the synapse maturation process. The work is published in the latest issue of Neuron (R. Jüttner et al. Impaired synapse function during postnatal development in the absence of CALEB, an EGF-like protein processed by neuronal activity. Neuron 46, (2), 21 April 2005, p. 233-245.

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Pamela Cohen
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