Kinesin Family of Proteins Kif11 and Kif21B Act as Inhibitory Constraints of Excitatory Synaptic Transmission Through Distinct Mechanisms

Despite our understanding of the functions of the kinesin family of motor proteins (Kifs) in neurons, their specific roles in neuronal communication are less understood. To address this, by carrying out RNAi-mediated loss of function studies, we assessed the necessity of 18 Kifs in excitatory synaptic transmission in mouse primary hippocampal neurons prepared from both sexes. Our measurements of excitatory post-synaptic currents (EPSCs) have identified 7 Kifs that were found to be not critical and 11 Kifs that are essential for synaptic transmission by impacting either frequency or amplitude or both components of EPSCs. Intriguingly we found that knockdown of mitotic Kif4A and Kif11 and post-mitotic Kif21B resulted in an increase in EPSCs suggesting that they function as inhibitory constraints on synaptic transmission. Furthermore, Kifs (11, 21B, 13B) with distinct effects on synaptic transmission are expressed in the same hippocampal neuron. Mechanistically, unlike Kif21B, Kif11 requires the activity of pre-synaptic NMDARs. In addition, we find that Kif11 knockdown enhanced dendritic arborization, synapse number, expression of synaptic vesicle proteins synaptophysin and active zone protein Piccolo. Moreover, expression of Piccolo constrained Kif11 function in synaptic transmission. Together these results suggest that neurons are able to utilize specific Kifs as tools for calibrating synaptic function. These studies bring novel insights into the biology of Kifs and functioning of neural circuits.