The KIF1A homolog Unc-104 is important for spontaneous release, postsynaptic density maturation and perisynaptic scaffold organization.
The kinesin-3 family member KIF1A has been shown to be important for experience dependent neuroplasticity. In Drosophila, amorphic mutations in the KIF1A homolog unc-104 disrupt the formation of mature boutons. Disease associated KIF1A mutations have been associated with motor and sensory dysfunctions as well as non-syndromic intellectual disability in humans. A hypomorphic mutation in the forkhead-associated domain of Unc-104, unc-104bris, impairs active zone maturation resulting in an increased fraction of post-synaptic glutamate receptor fields that lack the active zone scaffolding protein Bruchpilot. Here, we show that the unc-104brismutation causes defects in synaptic transmission as manifested by reduced amplitude of both evoked and miniature excitatory junctional potentials. Structural defects observed in the postsynaptic compartment of mutant NMJs include reduced glutamate receptor field size, and altered glutamate receptor composition. In addition, we observed marked loss of postsynaptic scaffolding proteins and reduced complexity of the sub-synaptic reticulum, which could be rescued by pre- but not postsynaptic expression of unc-104. Our results highlight the importance of kinesin-3 based axonal transport in synaptic transmission and provide novel insights into the role of Unc-104 in synapse maturation.
Junior Research Group Synaptic Plasticity, Hertie-Institute for Clinical Brain Research, University of Tübingen, Otfried-Müller-Str. 27, 72076 Tübingen 72076, Germany.|Graduate School of Cellular and Molecular Neuroscience, University of Tübingen, 72074 Tübingen, Germany.|The Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Yao V
YV
Zhang
Junior Research Group Synaptic Plasticity, Hertie-Institute for Clinical Brain Research, University of Tübingen, Otfried-Müller-Str. 27, 72076 Tübingen 72076, Germany.|Graduate School of Cellular and Molecular Neuroscience, University of Tübingen, 72074 Tübingen, Germany.|CHS Research Group Proteostasis in Neurodegenerative Disease at CellNetworks Heidelberg University and DKFZ Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 581, 69120 Heidelberg, Germany.
Shabab B
SB
Hannan
Junior Research Group Synaptic Plasticity, Hertie-Institute for Clinical Brain Research, University of Tübingen, Otfried-Müller-Str. 27, 72076 Tübingen 72076, Germany.
Jeannine V
JV
Kern
Junior Research Group Synaptic Plasticity, Hertie-Institute for Clinical Brain Research, University of Tübingen, Otfried-Müller-Str. 27, 72076 Tübingen 72076, Germany.
Doychin T
DT
Stanchev
Graduate School of Cellular and Molecular Neuroscience, University of Tübingen, 72074 Tübingen, Germany.
Baran
B
Koç
CHS Research Group Proteostasis in Neurodegenerative Disease at CellNetworks Heidelberg University and DKFZ Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 581, 69120 Heidelberg, Germany.
Thomas R
TR
Jahn
Junior Research Group Synaptic Plasticity, Hertie-Institute for Clinical Brain Research, University of Tübingen, Otfried-Müller-Str. 27, 72076 Tübingen 72076, Germany.|CHS Research Group Proteostasis in Neurodegenerative Disease at CellNetworks Heidelberg University and DKFZ Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 581, 69120 Heidelberg, Germany.
Tobias M
TM
Rasse
D000818:Animals; D004330:Drosophila / Q000378:metabolism* / Q000648:ultrastructure; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D007814:Larva; D009154:Mutation; D009469:Neuromuscular Junction / Q000378:metabolism; D057907:Post-Synaptic Density; D009435:Synaptic Transmission
D029721:Drosophila Proteins; C587248:Unc-104 protein, Drosophila; D016547:Kinesins