Presynaptic development is controlled by the core active zone proteins CAST/ELKS

Abstract Many presynaptic active zone proteins have multiple regulatory roles that vary during distinct stages of neuronal circuit development. However, our understanding how presynaptic active zone proteins regulate synapse development during neuronal circuit maturation is in its early stages. Although CAST/ELKS are presynaptic active zone core proteins, their roles in synapse development in the mammalian central nervous system remain enigmatic. To unravel CAST/ELKS roles in glutamatergic synapse development, we analyzed how their loss during the early stages of circuit maturation impacted the calyx of Held presynaptic terminal development and function. We found a reduction in presynaptic surface area and volume, but an increase in active zone size. Additionally, we found a reduction in all presynaptic Cav2 channel subtype currents. Surprisingly, these changes did not impair synaptic transmission. We propose that CAST/ELKS are involved in pathways regulating presynaptic morphological properties and Cav2 channel subtype levels during early stages of neuronal circuit maturation.