Central nervous system (CNS) synapse formation is a complex process that ensures precise alignment, as well as complementarity of the presynaptic and postsynaptic components. Numerous players are involved in different stages of CNS synaptogenesis, however, the list is far from complete. Neuregulin-1 (NRG1) and its receptor ErbB4 tyrosine kinase are widely expressed in the developing and adult brain. ErbB4 is specifically expressed in inhibitory GABAergic interneurons. Moreover, ErbB4 is localized to synapses and associates through it PDZ-binding motif with the postsynaptic density protein PSD-95, a major scaffolding protein involved in glutamatergic synapse stabilization and maturation. Given its location, ErbB4 is capable to take part in synapse development in GABAergic interneurons; however, little is known of its function at the synapse.
In the following work, we manipulated levels of ErbB4 protein expression in primary hippocampal neuron cultures to determine the role of ErbB4 at the synapse. We found that cells overexpressing the receptor formed larger excitatory and inhibitory presynaptic terminals, while the number of synapses per unit length remained the same. This process did not depend on the kinase domain activity. Moreover, highly clustered exogenous ErbB4 recruited PSD-95 to the site of the synapse, a process dependent on the PDZ interaction, since deletion of the PDZ binding motif severely perturbed ErbB4 localization. However, ErbB4 is not a synapse inducing factor, since expression in heterologous cells failed to induce presynaptic differentiation.Medicine, Faculty ofGraduat
