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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.

Among the subtypes of the Ca2+-dependent protein kinase C (PKC), which play a crucial role in long-term depression (LTD), both alpha and gamma are expressed in the cerebellar floccular Purkinje cells. To reveal the functional differences of PKC subtypes, we examined the adaptability of ocular reflexes of PKCgamma mutant mice, which show mild ataxia and normal LTD. In mutant mice, gains of the horizontal optokinetic eye response (HOKR) were reduced. Adaptation of the HOKR was not affected but its retinal slip dependency was altered in mutant mice. Sustained 1-h sinusoidal screen oscillation, which induced a relatively large amount of retinal slips in both mutant and wild-type mice, increased the HOKR gain in wild-type mice but not in mutant mice. In contrast, exposure to 1 h of sustained slower screen oscillations, which induced relatively small retinal slips in mutant and wild-type mice, increased the HOKR gain in both mutant and wild-type mice. Adaptation of the HOKR of the mutant mice to slow screen oscillation and those of wild-type mice to fast and slow screen oscillations were all abolished by local applications of a PKC inhibitor (chelerythrine) within the flocculi. Electrophysiological and anatomical studies showed no appreciable changes in the sources and magnitudes of climbing fibre inputs, which mediate retinal slip signals to the flocculus in the mutant mice. These results suggest that PKCgamma has a modulatory role in determining retinal slip dependency, and other PKC subtypes, e.g. PKCalpha, may play a crucial role in the adaptation of the HOKR.

Introduction An essential complement to molecular-genetic approaches for analyzing the function of the oculomotor circuitry in mice is an understanding of sensory and motor signal processing in the circuit. Although there has been extensive analysis of the signals carried by neurons in the oculomotor circuits of species, such as monkeys, rabbits and goldfish, relatively little in vivo physiology has been done in the oculomotor circuitry of mice. We analyzed the contribution of vestibular and nonvestibular signals to the responses of individual Purkinje cells in the cerebellar flocculus of mice. Methods We recorded Purkinje cells in the cerebellar flocculus of C57 BL/6 mice during eye movement responses to vestibular and visual stimulation. Results As in other species, most individual Purkinje cells in mice carried both vestibular and nonvestibular signals, and the most common response across cells was an increase in firing in response to ipsiversive eye movement or ipsiversive head movement. When both the head and eyes were moving, the Purkinje cell responses were approximated as a linear summation of head and eye velocity inputs. Unlike other species, floccular Purkinje cells in mice were considerably more sensitive to eye velocity than head velocity. Conclusions The signal content of Purkinje cells in the cerebellar flocculus of mice was qualitatively similar to that in other species. However, the eye velocity sensitivity was higher than in other species, which may reflect a tuning to the smaller range of eye velocities in mice. [ABSTRACT FROM AUTHOR]

The ionotropic glutamate receptorδ2 subunit (GluRδ2) is selectively expressed in cerebellar Purkinje cells and is implicated in long-term depression, synaptic formation and elimination. To study the effect of GluRδ2 deficiency on motor control, we measured the vestibulo-ocular reflex (VOR) and optokinetic response (OKR) induced by sinusoidal rotation of the animal and/or the surrounding screen in two GluRδ2 mutant mice: a GluRδ2 knockout mouse (δ2–/–) and alurchermouse with a point mutation in the GluRδ2 gene resulting in loss of all Purkinje cells.δ2–/– showed significantly higher VOR gain in the dark (VORD) than in the wild-type. Inδ2–/–, the VOR gain in light was lower than that in the dark. The phase of OKR lagged more inδ2–/– than inlurcherand wild-type mice. Both mutant mice failed to change the VORD or OKR gain adaptively in response to sustained vestibular and/or visual stimulation. Basal properties of VOR and OKR changed little by lesion of the flocculus, but they changed substantially by lesion of the inferior olivary nuclei (IO). The abnormal VOR gain and OKR phase delay were clearly reduced inδ2–/– by the latter lesion. Our results indicate that failures in the GluRδ2-dependent synaptic regulation affect motor performance more severely than loss of cerebellar cortical outputs. This study suggests that the anomalies inδ2–/– are dependent on inputs from IO and that GluRδ2 deficiency changed properties of not only the cerebellar cortex but also the brainstem neuronal pathways controlling reflex eye movements during development. [ABSTRACT FROM AUTHOR]

Metabotropic glutamate receptor subtype 1 (mGluR1) plays an essential role in the cerebellar long-term depression (LTD). We examined the dynamic characteristics and adaptability of horizontal vestibulo-ocular reflex (HVOR) and optokinetic response (HOKR) eye movements in mGluR1 knockout mice. A mild difference was seen in the HOKR/HVOR dynamics between the wild-type and mGluR1(−/−) mice. Exposure to 1 h of sustained screen oscillation, which induced HOKR adaptation in wild-type mice, induced no change in mutant mice. These results suggest that the mGluR1 plays an essential role in the adaptation of HOKR, and LTD underlies the adaptation of ocular reflexes. [Copyright &y& Elsevier]

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]