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The brain-specific protein, Seizure‐related gene‐6 (Sez-6), plays an important role in the development of appropriate neuronal circuitry in the mammalian central nervous system. Especially, Sez-6 is an essential regulator of dendritic branching, dendritic spine formation and excitatory synapse numbers.

In this manner Sez-6 knockout (Sez-6 -/-) animals have been shown to possess morphologically different neurons and dendritic arborization. Indeed, Sez-6 -/- mice exhibit an excess of short dendrites, an excessive neurite branching and a reduced spine density relative to wild-type (WT) neurons. Similarly, a greater proportion of spines were observed on dendrites of control cortical neurons than on Sez-6 -/- neurons.

Based on these morphological data, we have simulated the importance of Sez-6 in signal integration processes of the neurons. We show that dendritic arborization of Sez6 -/- animals would be a more effective integrator of stimuli that occur at the same time (temporal integration) and at different locations (spatial integration). Indeed, the ability of neurons to receive and integrate synaptic information depends to an extent on their dendritic morphology. However, when the previously announced decreasing number of synapses for Sez 6 -/- was involved in the model, the quality of the signal integration process was drastically reduced.

The signal transduction could also be impacted by endosomal trafficking which is a key mechanism that drives nascent synapse development. The transmembrane cell-surface isoform Sez-6 tII can undergo endocytosis. Transmembrane proteins are continuously shuttled from the endosomal compartment to the neuronal plasma membrane by highly regulated and complex trafficking steps. These events are involved in many homeostatic and physiological processes such as neuronal growth, signaling, learning and memory among others. However, whether the trafficking and cell-surface distribution of Sez-6 is regulated, and how transmembrane Sez-6 is distributed amongst these various compartments, is not known. In the case of Sez-6, the neuronal sorting nexins SNX17 and SNX27 could be involved in regulating its function as they recognize amino acid motifs similar to those in the cytoplasmic tail of Sez-6 tII. We show here that the distribution of Sez-6 and SNXs exhibits partial overlap with the early endosome and that Sez-6 is partially localized in the recycling endosome. Furthermore we provide evidence for interaction of Sez-6 and SNX27.

Considering our results, the importance of receptor trafficking in the maturation of synapses, plus the interactions of SNXs with Sez-6 and finally the signal integration processes of the neurons might play an important role in the development of dendrites and synapses as well as the connection circuits in the nervous system.