Optogenetic Control of Synaptic AMPA Receptor Endocytosis Reveals Roles of LTD in Motor Learning

Long-term depression (LTD) of AMPA-type glutamate receptor (AMPA receptor)-mediated synaptic transmission has been proposed as a cellular substrate for learning and memory. Although activity-induced AMPA receptor endocytosis is believed to underlie LTD, it remains largely unclear whether LTD and AMP...

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Bibliographic Details
Published in:Neuron (Cambridge, Mass.) Mass.), 2018-09, Vol.99 (5), p.985-998.e6
Main Authors: Kakegawa, Wataru, Katoh, Akira, Narumi, Sakae, Miura, Eriko, Motohashi, Junko, Takahashi, Akiyo, Kohda, Kazuhisa, Fukazawa, Yugo, Yuzaki, Michisuke, Matsuda, Shinji
Format: Article
Language:English
Subjects:
AMPA receptor
Animals
Cells, Cultured
Cerebellar plasticity
Cerebellum
Endocytosis
Endocytosis - physiology
Experiments
Glutamic acid receptors
HEK293 Cells
Humans
Labeling
Learning - physiology
Light
Long-term depression
Long-Term Synaptic Depression - physiology
Memory
Mice
Mice, Inbred C57BL
Mice, Inbred ICR
Motor Activity - physiology
Motor skill learning
Neurons
optogenetics
Optogenetics - methods
Optokinetic response
Organ Culture Techniques
Purkinje cell
Purkinje cells
Purkinje Cells - chemistry
Purkinje Cells - physiology
Receptors, AMPA - analysis
Receptors, AMPA - physiology
Software
Synaptic plasticity
Synaptic transmission
Vestibulo-ocular reflex
α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
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Summary:Long-term depression (LTD) of AMPA-type glutamate receptor (AMPA receptor)-mediated synaptic transmission has been proposed as a cellular substrate for learning and memory. Although activity-induced AMPA receptor endocytosis is believed to underlie LTD, it remains largely unclear whether LTD and AMPA receptor endocytosis at specific synapses are causally linked to learning and memory in vivo. Here we developed a new optogenetic tool, termed PhotonSABER, which enabled the temporal, spatial, and cell-type-specific control of AMPA receptor endocytosis at active synapses, while the basal synaptic properties and other forms of synaptic plasticity were unaffected. We found that fiberoptic illumination to Purkinje cells expressing PhotonSABER in vivo inhibited cerebellar motor learning during adaptation of the horizontal optokinetic response and vestibulo-ocular reflex, as well as synaptic AMPA receptor decrease in the flocculus. Our results demonstrate that LTD and AMPA receptor endocytosis at specific neuronal circuits were directly responsible for motor learning in vivo. [Display omitted] [Display omitted] •A new optogenetic tool, PhotonSABER, controls endocytosis at active synapses•PhotonSABER inhibits AMPA receptor endocytosis during LTD in a light-dependent manner•Basal synaptic transmission and other forms of synaptic plasticity were unaffected•PhotonSABER inhibits AMPA receptor endocytosis and motor learning in Purkinje cells in vivo Kakegawa et al. show that AMPA receptor endocytosis at parallel fiber-Purkinje cell synapses in the cerebellar flocculus plays a direct role in motor learning in vivo, using a new optogenetic tool, PhotonSABER, which enables the acute inhibition of AMPA receptor endocytosis during LTD.
ISSN:0896-6273
1097-4199
DOI:10.1016/j.neuron.2018.07.034