DPP6 regulation of dendritic morphogenesis impacts hippocampal synaptic development

Dipeptidyl-peptidase 6 is an auxiliary subunit of Kv4-mediated A-type K + channels that, in addition to enhancing channel surface expression, potently accelerates their kinetics. The dipeptidyl-peptidase 6 gene has been associated with a number of human central nervous system disorders including autism spectrum disorders and schizophrenia. Here we employ knockdown and genetic deletion of dipeptidyl-peptidase 6 to reveal its importance for the formation and stability of dendritic filopodia during early neuronal development. We find that the hippocampal neurons lacking dipeptidyl-peptidase 6 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 dipeptidyl-peptidase 6 interacts with a filopodia-associated myosin as well as with fibronectin in the extracellular matrix. dipeptidyl-peptidase 6 therefore has an unexpected but important role in cell adhesion and motility, impacting the hippocampal synaptic development and function. Dipeptidyl-peptidase 6 is implicated in different neuropsychiatric pathologies. Lin and colleagues genetically delete dipeptidyl-peptidase 6 in mice and find that this results in impaired development of dendritic filopodia, as well as a reduction in the dendritic tree size, spine density and functional synapses.