Specific depletion of the motor protein KIF5B leads to deficits in dendritic transport, synaptic plasticity and memory

Abstract

Kinesin and dynein superfamily of proteins are microtubule-dependent molecular motors that mediate long-distance transport of materials in neuron. The kinesin superfamily is very diverse and contains 45 members in mammal. One key question that is not well-addressed is whether and how the different kinesin motors exhibit functional specificity. Gene duplication and subsequent diversification give rise to three homologous kinesin I proteins (KIF5A, KIF5B and KIF5C) in vertebrates. They were initially regarded to be functionally redundant because of their conserved cargo-binding domains, but specificity between KIF5A and the other two KIF5s has been reported in axonal transport in zebrafish. Previous studies on KIF5s have mostly focused on axonal transport, while the roles of kinesin I in dendritic transport and postsynaptic function are less well-defined. Here we show that acute knockdown of KIF5A or KIF5B by RNA-interference differentially affects excitatory synapses and dendritic transport in rodent hippocampal neurons. Because of the embryonic lethality of KIF5B knockout mice that precludes their use to study the synaptic and cognitive functions of adult brain in vivo, we generate conditional knockout mice with specific depletion of KIF5B in excitatory neurons after birth. These KIF5B-deficient mice exhibit altered dendritic spine morphogenesis in the hippocampus, together with impaired hippocampal long-term potentiation and memory formation. Our findings reveal the unexpected functional specificity between two homologous motor proteins, and provide new insights into how expansion of the kinesin I family during evolution leads to diversification and specialization of motor proteins in neuron.