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Microtubule dynamics at synaptic contacts are modulated by neuronal activity and affected by oligomeric Abeta 1-42

on the January 7, 2020

Seminar by Francesca Bartolini (Columbia University Medical Center, New York)

Emerging studies from several groups have indicated that dynamic microtubules (MTs), in addition to modified MTs, play key roles in neuronal function. In addition, synaptic biphasic fluctuations of MT instability/stability and tubulin post-translational modifications (PTMs) are associated with memory formation and are disrupted in aging, indicating a primary role for the regulation of MT dynamics and tubulin PTMs in the maintenance of synaptic plasticity. In support of this model, we recently found that stabilization of dynamic MTs and induction of tubulin PTMs by the formin mDia1 contribute to oligomeric A?1-42 synaptotoxicity, and inhibition of MT dynamics alone is sufficient to promote tau hyperphosphorylation and tau dependent synaptotoxicity (Qu et al., J Cell Biol, 2017). To test whether these changes occur at synapses and are directly responsible for synapse loss, we have further developed microscopy assays that measure MT invasions into dendritic spines and MT contacts with single presynaptic boutons of hippocampal neurons in culture. Surprisingly, we found that dynamic MT plus ends preferentially grow near presynaptic boutons, and rescue/nucleation at boutons is enhanced by neurotransmitter release or when neurons are challenged with oligomeric A?1-42 (A?), an activity mediated by tau. A? also acutely affected the fraction of spines invaded by MTs, which appeared to be the most resistant to injury-dependent structural plasticity. Our data underscore the existence of a previously uncharacterized pool of presynaptic dynamic MTs that respond to neurotransmission and excitotoxicity, and reveal a function for spine-invading MTs in conferring resistance to pruning.
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