Cellular and Molecular Synaptic Function Unit, Okinawa Institute of Science and Technology - Graduate University, Okinawa, Japan; Faculty of Life and Medical Sciences, Doshisha University, Kyoto, Japan
Cellular and Molecular Synaptic Function Unit, Okinawa Institute of Science and Technology - Graduate University, Okinawa, Japan; Institute of Science and Technology Austria (IST Austria), Klosterneuburg, Austria
Cellular and Molecular Synaptic Function Unit, Okinawa Institute of Science and Technology - Graduate University, Okinawa, Japan; Molecular Neuroscience Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan
Zacharie Taoufiq
Cellular and Molecular Synaptic Function Unit, Okinawa Institute of Science and Technology - Graduate University, Okinawa, Japan
Satyajit Mahapatra
Cellular and Molecular Synaptic Function Unit, Okinawa Institute of Science and Technology - Graduate University, Okinawa, Japan
Hiroshi Yamada
Department of Neuroscience, Graduate school of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
Kohji Takei
Department of Neuroscience, Graduate school of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
Elevation of soluble wild-type (WT) tau occurs in synaptic compartments in Alzheimer’s disease. We addressed whether tau elevation affects synaptic transmission at the calyx of Held in slices from mice brainstem. Whole-cell loading of WT human tau (h-tau) in presynaptic terminals at 10–20 µM caused microtubule (MT) assembly and activity-dependent rundown of excitatory neurotransmission. Capacitance measurements revealed that the primary target of WT h-tau is vesicle endocytosis. Blocking MT assembly using nocodazole prevented tau-induced impairments of endocytosis and neurotransmission. Immunofluorescence imaging analyses revealed that MT assembly by WT h-tau loading was associated with an increased MT-bound fraction of the endocytic protein dynamin. A synthetic dodecapeptide corresponding to dynamin 1-pleckstrin-homology domain inhibited MT-dynamin interaction and rescued tau-induced impairments of endocytosis and neurotransmission. We conclude that elevation of presynaptic WT tau induces de novo assembly of MTs, thereby sequestering free dynamins. As a result, endocytosis and subsequent vesicle replenishment are impaired, causing activity-dependent rundown of neurotransmission.