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Speech is a complex sensorimotor skill, and vocal learning involves both the basal ganglia and the cerebellum. These subcortical structures interact indirectly through their respective loops with thalamo-cortical and brainstem networks, and directly via subcortical pathways, but the role of their interaction during sensorimotor learning remains undetermined. While songbirds and their song-dedicated basal ganglia-thalamo-cortical circuitry offer a unique opportunity to study subcortical circuits involved in vocal learning, the cerebellar contribution to avian song learning remains unknown. We demonstrate that the cerebellum provides a strong input to the song-related basal ganglia nucleus in zebra finches. Cerebellar signals are transmitted to the basal ganglia via a disynaptic connection through the thalamus and then conveyed to their cortical target and to the premotor nucleus controlling song production. Finally, cerebellar lesions impair juvenile song learning, opening new opportunities to investigate how subcortical interactions between the cerebellum and basal ganglia contribute to sensorimotor learning., Competing Interests: LP, PL, CL, AL No competing interests declared, (© 2018, Pidoux et al.)

A classic view in cerebellar physiology holds that Purkinje cells do not express functional NMDA receptors and that, therefore, postsynaptic NMDA receptors are not involved in the induction of long-term depression (LTD) at parallel fiber (PF) to Purkinje cell synapses. Recently, it has been demonstrated that functional NMDA receptors are postsynaptically expressed at climbing fiber (CF) to Purkinje cell synapses in mice, reaching full expression levels at ∼2 months after birth. Here, we show that in the mature mouse cerebellum LTD (induced by paired PF and CF activation), but not long-term potentiation (LTP; PF stimulation alone) at PF to Purkinje cell synapses is blocked by bath application of the NMDA receptor antagonist D-2-amino-5-phosphonovaleric acid (D-APV). A blockade of LTD, but not LTP, was also observed when the noncompetitive NMDA channel blocker MK-801 was added to the patch-pipette saline, suggesting that postsynaptically expressed NMDA receptors are required for LTD induction. Using confocal calcium imaging, we show that CF-evoked calcium transients in dendritic spines are reduced in the presence of D-APV. This observation confirms that NMDA receptor signaling occurs at CF synapses and suggests that NMDA receptor-mediated calcium transients at the CF input site might contribute to LTD induction. Finally, we performed dendritic patch-clamp recordings from rat Purkinje cells. Dendritically recorded CF responses were reduced when D-APV was bath applied. Together, these data suggest that the late developmental expression of postsynaptic NMDA receptors at CF synapses onto Purkinje cells is associated with a switch toward an NMDA receptor-dependent LTD induction mechanism.

Immature Purkinje neurons are particularly vulnerable cells. They survive in cerebellar slice cultures under treatment by the synthetic steroid mifepristone (RU486) that depolarizes diem at this age. The present study aims at understanding die mechanism underlying this neuroprotective effect. In the developing cerebellum, die role of γ-aminobutyric acid (GABA) in neuron survival is unknown. In 3-d-old mouse cerebellar slice cultures, we show that GABAA receptor activation is depolarizing and excitatory. Antagonists of GABAA receptors rescue Purkinje neurons, demonstrating that GABA is endogenously released hi tins preparation and is toxic. Mifepristone likely protects these neurons by reversing GABAA receptor-mediated chloride fluxes and reducing their driving force. Neuroprotection by mifepristone is dose-dependently decreased by the agonist of GABAA receptors muscimol and by caffeine, an agonist of internal calcium store release. Moreover, the survival induced by neomycin, an inhibitor of calcium release, is partially reversed by muscimol. The p38 mitogen-activated protein kinase (MAPK) inhibitor SB239063 also rescues Purkinje neurons. In summary, we propose that when GABA is depolarizing, mifepristone protects Purkinje neurons by shunting GABA responses and probably chloride fluxes, by inhibiting p38 MAPK activity and likely internal calcium store release. A new and nonhormonal effect of mifepristone is thus revealed. [ABSTRACT FROM AUTHOR]

Among integrative neurons displaying long-term synaptic plasticity, adult Purkinje cells seemed to be an exception by lacking functional NMDA receptors (NMDA-Rs). Although numerous anatomical studies have shown both NR1 and NR2 NMDA-R subunits in adult Purkinje cells, patch-clamp studies failed to detect any NMDA currents. Using more recent pharmacological and immunodetection tools, we demonstrate here that Purkinje cells from adult mice respond to exogenous NMDA application and that postsynaptic NMDA-Rs carry part of the climbing fiber-mediated EPSC (CF-EPSC), with undetectable contribution from presynaptic or polysynaptic NMDA currents. We also detect NR2-A/B subunits in adult Purkinje cells by immunohistochemistry. The NMDA-mediated CF-EPSC is barely detectable before 3 weeks postnatal. From the end of the third week, the number of cells displaying the NMDA-mediated CF-EPSC rapidly increases. Soon, this EPSC becomes detectable in all the Purkinje cells but is still very small. Its amplitude continues to increase until 12 weeks after birth. In mature Purkinje cells, we show that the NMDA-Rs contribute to the depolarizing plateau of complex spikes and increase their number of spikelets. Together, these observations demonstrate that mature Purkinje cells express functional NMDA receptors that become detectable in CF-EPSCs at ∼21 d after birth and control the complex spike waveform. [ABSTRACT FROM AUTHOR]

Summarizes the cellular mechanisms of the cerebellar long-term depression (LTD) of synaptic transmission at parallel fiber-Purkinje cell synapses in the cerebellum. Experiments conducted on the cellular mechanisms of LTD; Sources and targets of nitrogen oxide; Conclusion of the experiment. INSETS: Box 1. Glutamatergic receptors involved in LTD induction;Box 2. Involvement of protein kinase C (PKC) activation and....