KIF2C and receptor trafficking: Cerebellar synapses show the way

It is well established that microtubules (MTs) are essential for cargo trafficking to the synapse, and that abnormal MT dynamics are associated with neural dysfunction. MTs are highly dynamic, polar structures along which cargo is transported by molecular motors such as kinesins. Unlike other kinesins, the main function of the kinesin-13 family member KIF2C/MCAK (mitotic centromere-associated kinesin) is to depolymerize MTs and thereby regulate their dynamics (Wordeman, 2005). However, the role of KIF2C in the brain, and more specifically in trafficking receptors to the synapse in neurons, is poorly understood. The recent study by Zheng et al. (2023) demonstrates that Purkinje cell-specific loss of KIF2C affects trafficking and surface expression of glutamate receptors, thereby regulating excitatory synaptic transmission and cerebellum-dependent behaviour. In a previous study, Zheng et al. (2022) had laid the framework for the present study by demonstrating that KIF2C is highly expressed in the brain and that loss of KIF2C leads to changes in MT dynamics in hippocampal neurons. Critically, this resulted in an increase in surface expression of the excitatory glutamatergic AMPA receptor in the hippocampus. In the present study, to determine the role of KIF2C in cerebellar synapses, Zheng et al. (2023) created a conditional knockout (cKO) of KIF2C in postnatal Purkinje cells. Notwithstanding the role of KIF2C in MT depolymerization, cKO mice had no differences in gross anatomy of the cerebellum, or in Purkinje cell dendritic and spine structure. This is perhaps surprising in light of the previous observation that spine structure is changed in the hippocampus when KIF2C is knocked out, leading to deficits in the density and structure of mushroom-shaped spines. Their next observation, however, aligned well with results in the hippocampus: there was an increase in AMPAR-dependent synaptic transmission at Purkinje cell synapses, which appears to be due to an increase in postsynaptic receptors (the GluA2 subunit specifically), rather than presynaptic release. A key finding of the current study by Zheng et al. (2023) is that, in contrast to the increase in ionotropic, AMPAR-dependent transmission upon KIF2C loss, synaptic transmission through the metabotropic glutamate receptor 1 (mGlu1) is decreased because of reduced mGlu1 receptors on the postsynaptic membrane. In addition, there is evidence of changes in the internalization-to-recycling pathway triggered upon mGlu1 agonist binding. These results highlight the differential regulation of glutamatergic receptors by KIF2C in Purkinje cells. While the increase in surface GluA2 was linked to increased KIF5B-dependent transport, the authors suggest that the decreased mGlu1 surface expression was due to an interaction between KIF2C and Rab8, which is a small GTPase known to play a role in mGlu surface expression. However, the exact mechanisms by which KIF2C together with Rab8 controls mGlu trafficking remain unknown. In addition, Rab8 is generally important for receptor trafficking from the endoplasmic reticulum-Golgi network along MTs to the postsynaptic membrane and has been implicated in AMPAR trafficking as well (Gerges et al., 2004). Conversely, KIF5 may also be involved in mGlu trafficking (Bodzęta et al., 2021). It is noteworthy that mGlus can themselves regulate the trafficking of AMPARs, which is not investigated here. In contrast to the effects on excitatory synaptic transmission, there was no effect of KIF2C loss on GABAergic inhibitory synaptic transmission. In addition, the effects of KIF2C loss on MT dynamics in the cerebellum are not yet known. Finally, Zheng et al. (2023) went on to demonstrate that cKO mice had impairments in motor performance and adaptation, in tests widely linked to cerebellar function. In contrast, there were no changes in social behaviour. Given that the cerebellum has many non-motor roles, including social behaviours, these results suggest a selectivity of the deficit that warrants further investigation and might suggest regional variability, as well as provide insight into cerebellar function. Taken together, the recent findings on KIF2C open up a range of fascinating questions. What happens to synaptic plasticity in the cerebellum? KIF2C loss results in a deficit in long-term potentiation (LTP) in the hippocampus, but the effect on cerebellar plasticity remains unknown. The hippocampal findings raise the possibility of links between the deficits in LTP and in spine shape. In the cerebellum, in addition to the existence of LTP, long-term depression (LTD) at parallel fibre synapses onto Purkinje cells is important for cerebellar function, and relies both on mGlu1 and on AMPARs. How do KIF2C, the regulation of MT dynamics and glutamate receptor expression interact in the context of synaptic plasticity? Overall, the study by Zheng et al. (2023) raises many broader questions. What exactly are the signalling pathways, structural associations, and regulatory mechanisms that link KIF2C to surface expression of both ionotropic and metabotropic glutamate receptors? Critically, given the role of KIF2C in the regulation of MT dynamics, what other aspects of cellular trafficking are modified? It appears that the alteration in MT dynamics affects spine structure, at least in the hippocampus. Therefore, are other cytoskeletal players such as actin are affected by loss of KIF2C too? Also, mGlu surface expression depends on many players (Bodzęta et al., 2021). Is their intracellular transport perturbed by KIF2C knockout? A key future question is how KIF2C regulates synapses over development or in the face of experience-dependent change. Furthermore, KIF2C itself has many regulators in the context of mitosis. How might it be regulated during neural development and plasticity? In summary, the recent study by Zheng et al. (2023) highlights the role of KIF2C in the postsynaptic expression of glutamate receptors and gives rise to a range of exciting new questions whose investigation will be fundamental for our understanding of synaptic function. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. No competing interests declared A.S. and F.M. were responsible for the conception or design of the work; drafting the work or revising it critically for important intellectual content; and final approval of the version to be published. Both authors agree to be accountable for all aspects of the work. FRQ | Fonds de Recherche du Québec – Santé (FRQS): Aparna Suvrathan, Chercheurs-boursiers Junior Award #266 531; Research Institute of the McGill University Health Centre Studentship Award: Franziska Mudlaff, NA; Gouvernement du Canada | Canadian Institutes of Health Research (IRSC): Aparna Suvrathan, 178 281 There is no grant reference number for the Studentship Award to Franziska Mudlaff.

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