A critical function for Microtubule-Associated Protein 6 in activity-dependent stabilisation of actin filaments in dendritic spines

BISBAL M; JONCKHEERE J; BOSC C; DELOULME C; GOLDBERG Y; ANDRIEUX A; PERIS L; SAOUDI Y; DENARIER E; GORY-FAURÉ S; ARNAL I; DELPHIN C; HERNANDEZ-MARTINEZ J; BROCARD J; GUERIN C; BUISSON A; BLANCHOIN L

Heidelberg

Simposio; EMBO/EMBL Symposia: Microtubules: From Atoms to Complex Systems.; 2018

EMBO/EMBL

Synaptic modifications that underlie plasticity, learning and memory critically depend on the remodelling of actin filaments within dendritic spines, the neuronal membrane protrusions that support the post-synaptic side of most excitatory synapses in the adult brain. Along with actin-regulatory factors, accumulating evidence implicates microtubule-associated proteins (MAPs) in plasticity processes. As microtubules are only fleetingly present in spines, the question arises of how the different MAPs may contribute to remodelling of the post-synaptic cytoskeleton. Here, we address this question in the case of MAP6 (also known as STOP), a structural MAP with microtubule-stabilizing properties. MAP6 deficient mice exhibit striking deficits in plasticity and cognition. Using neurons from MAP6 KO mice, in vivo and in culture, we show that MAP6 is required for the maintenance of morphologically and functionally mature dendritic spines. Rescue experiments indicate that within the MAP6 sequence, the microtubule-binding repeats known as Mc modules are necessary and sufficient to restore spine integrity. While Mc modules are unable to bind microtubules at physiological temperature, we find that they directly bind actin filaments in neurons and in vitro. Further, we show that Mc modules mediate F-actin stabilisation in dendritic spines in response to synaptic excitation, a key event of synaptic plasticity. Activity-induced phosphorylation of MAP6 likely dissociates the protein from microtubules, allowing its transfer to the spine cytoskeleton. In in vitro assays, Mc modules enhanced actin filament nucleation and also promoted the formation of stable, rigid, highly ordered filament bundles. The actin-stabilizing effect of MAP6 during plasticity events provide a molecular explanation for its crucial role in cognition, enlightening the direct connection between dysfunctional cytoskeleton elements and impaired synaptic plasticity as observed in neuropsychiatric illnesses