Search

To optimize motor performance, both the amplitude and temporal properties of movements should be modifiable by motor learning. Here we report that the modification of movement timing is highly dependent on signaling through P/Qtype voltage-dependent calcium channels. Two lines of mutant mice heterozygous for P/Q-type voltage-dependent calcium channels exhibited impaired plasticity of eye movement timing, but relatively intact plasticity of movement amplitude during motor learning in the vestibulo-ocular reflex. The results thus demonstrate a distinction between the molecular signaling pathways regulating the timing versus amplitude of movements. [ABSTRACT FROM AUTHOR]

The cerebellum is an evolutionarily conserved structure critical for motor learning in vertebrates. The model that has influenced much of the work in the field for the past 30 years suggests that motor learning is mediated by a single plasticity mechanism in the cerebellum: long-term depression (LTD) of parallel fiber synapses onto Purkinje cells. However, recent studies of simple behaviors such as the vestibulo-ocular reflex (VOR) indicate that multiple plasticity mechanisms contribute to cerebellum-dependent learning. Multiple plasticity mechanisms may provide the flexibility required to store memories over different timescales, regulate the dynamics of movement, and allow bidirectional changes in movement amplitude. These plasticity mechanisms must act in combination with appropriate information-coding strategies to equip motor-learning systems with the ability to express learning in correct contexts. Studies of the patterns of generalization of motor learning in the VOR provide insight about the coding of information in neurons at sites of plasticity. These principles emerging from studies of the VOR are consistent with results concerning more complex behaviors and thus may reflect general principles of cerebellar function. [ABSTRACT FROM AUTHOR]

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. Video Abstract Graphical Abstract Highlights • 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. [ABSTRACT FROM AUTHOR]