DPP6 regulation of dendritic morphogenesis impacts hippocampal synaptic development

Dipeptidyl-peptidase 6 (DPP6) is an auxiliary subunit of Kv4-mediated A-type K(+) channels that, in addition to enhancing channel surface expression, potently accelerates their kinetics. The DPP6 gene has been associated with a number of human CNS disorders including ASDs and schizophrenia. Here we employ knockdown and genetic deletion of DPP6 to reveal its importance for the formation and stability of dendritic filopodia during early neuronal development. We find that hippocampal neurons lacking DPP6 show a sparser dendritic branching pattern along with fewer spines throughout development and into adulthood. In electrophysiological and imaging experiments we show that these deficits lead to fewer functional synapses and occur independently of the potassium channel subunit Kv4.2. We report that the extracellular domain of DPP6 interacts with a filopodia-associated myosin as well as with fibronectin in the extracellular matrix. DPP6 therefore plays an unexpected but important role in cell-adhesion and motility, impacting hippocampal synaptic development and function.