Transport of a kinesin-cargo pair along microtubules into dendritic spines undergoing synaptic plasticity

Abstract

Synaptic plasticity often involves changes in the structure and composition of dendritic spines. Vesicular cargos and organelles enter spines either by exocytosing in the dendrite shaft and diffusing into spines or through a kinesin to myosin hand-off at the base of spines. Here we present evidence for microtubule (MT)-based targeting of a specific motor/cargo pair directly into hippocampal dendritic spines. During transient MT polymerization into spines, the kinesin KIF1A and an associated cargo, synaptotagmin-IV (syt-IV), are trafficked in unison along MTs into spines. This trafficking into selected spines is activity-dependent and results in exocytosis of syt-IV-containing vesicles in the spine head. Surprisingly, knockdown of KIF1A causes frequent fusion of syt-IV-containing vesicles throughout the dendritic shaft and diffusion into spines. Taken together, these findings suggest a mechanism for targeting dendritic cargo directly into spines during synaptic plasticity and indicate that MT-bound kinesins prevent unregulated fusion by sequestering vesicular cargo to MTs.

Of microtubules and memory: implications for microtubule dynamics in dendrites and spines

“…The increased exocytosis that occurs throughout the dendritic arbor is followed by movement of exocytosed syt4 within the plane of the membrane. Together these results indicate that MTs are indeed capable of transporting specific cargo into targeted dendritic spines, and, of importance, this directed targeting of cargo is highly disrupted in the absence of a particular motor protein, KIF1A (McVicker et al , 2016). Thus not only are MTs important for transporting material throughout the dendritic arbor, but they are also instrumental in sequestering vesicles and cargo away from the plasma membrane while it is en route to its destination.…”

“…Four independent studies published within a year of one another demonstrated that MTs indeed enter spines in a synaptic activity–dependent manner (Gu et al , 2008; Hu et al , 2008; Mitsuyama et al , 2008; Jaworski et al , 2009). It is also clear, as demonstrated by live-cell microscopy, that all of the MT polymerization events into spines are transitory, averaging only a few minutes at a time (Hu et al , 2008, 2011; Jaworski et al , 2009; Kapitein et al , 2011; Merriam et al , 2011, 2013; Wagner et al , 2011; McVicker et al , 2016). Moreover, the presence of MTs in spines in fixed neurons required rapid fixation and the use of MT-stabilizing buffer (Gu et al , 2008; Hu et al , 2008; Mitsuyama et al , 2008).…”

“…Studies in our lab using hippocampal neurons confirmed that ER entry of spines is not a MT-based process (unpublished data). Moreover, our recent work suggests that mitochondria may also be using this actomyosin hand-off model to enter dendritic spines (McVicker et al , 2016; Figure 4). This raises a question: if MTs are not transporting ER into spines, then what are the potential cargoes entering spines along MT tracks?…”

“…However, a recent study documented a motor/cargo pair that uses MTs for entering dendritic spines. McVicker et al (2016) showed that the kinesin 3 motor KIF1A transports the synaptotagmin (syt) family member syt4 directly into spines along dynamic MTs. Once the syt4-containing vesicle enters a spine, it can exocytose in the spine head (Figure 4).…”

Loss of Bardet-Biedl syndrome proteins causes synaptic aberrations in principal neurons

“…The receptor transport to the spines becomes dependent on the other transport mechanisms (e.g. exocytosis of vesicles in the dendritic shafts or a myosin-based transport (40). As a result, reduced receptor signalling (e.g.…”