Abstract
The inferior olivary nucleus (IO) forms the gateway to the cerebellar cortex and receives feedback information from the cerebellar nuclei (CN), thereby occupying a central position in the olivo-cerebellar loop. Here, we investigated the feedback input from the CN to the IO in vivo in mice using the whole-cell patch-clamp technique. This approach allows us to study how the CN-feedback input is integrated with the activity of olivary neurons, while the olivo-cerebellar system and its connections are intact. Our results show how IO neurons respond to CN stimulation sequentially with: i) a short depolarization (EPSP), ii) a hyperpolarization (IPSP) and iii) a rebound depolarization. The latter two phenomena can also be evoked without the EPSPs. The IPSP is sensitive to a GABAA receptor blocker. The IPSP suppresses suprathreshold and subthreshold activity and is generated mainly by activation of the GABAA receptors. The rebound depolarization re-initiates and temporarily phase locks the subthreshold oscillations. Lack of electrotonical coupling does not affect the IPSP of individual olivary neurons, nor the sensitivity of its GABAA receptors to blockers. The GABAergic feedback input from the CN does not only temporarily block the transmission of signals through the IO, it also isolates neurons from the network by shunting the junction current and re-initiates the temporal pattern after a fixed time point. These data suggest that the IO not only functions as a cerebellar controlled gating device, but also operates as a pattern generator for controlling motor timing and/or learning.
Highlights
The inferior olive (IO) is located in the ventral medulla and gives rise to the climbing fibres (CFs), which constitute one of the two main excitatory inputs to the Purkinje cells (PCs) in the cerebellar cortex
The sinusoidal subthreshold oscillation is an intrinsic property [26,27,28], generate by a cascade of alternating channel activation [17] that includes the T-type Ca2+ channel CaV3.1.What emerged from our study is that both lowthreshold oscillations (LTO) and subthreshold oscillations (SSTO) neurons responded to cerebellar nuclei (CN) stimulation, but in a different manner
We stimulated two times in a row at different time intervals in four neurons that responded to CN stimulation with both a shortlatency excitatory postsynaptic potentials (EPSP) and a long-latency inhibitory postsynaptic potentials (IPSP) in order to elucidate for how long the IPSP can prevent the onset of the EPSP evoked by the second stimulation
Summary
The inferior olive (IO) is located in the ventral medulla and gives rise to the climbing fibres (CFs), which constitute one of the two main excitatory inputs to the Purkinje cells (PCs) in the cerebellar cortex. Part of the CN neurons projects directly to the IO via an inhibitory, GABAergic, pathway [2,3,4,5,6]; whereas another population of CN neurons excites the IO indirectly via nuclei located at the mesodiencephalic junction (MDJ) [7,8]. This olivo-cortico-nuclear projection (Figure 1A) forms the basis of the modular organization of the cerebellum [9]. The GABAergic feedback inhibition on the IO might serve to gate motor learning in the cerebellar cortex [2,12] or to control the participation of IO neurons in a motor task by controlling the electrical coupling between olivary neurons [13,14,15]
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