Synaptic excitation by climbing fibre collaterals in the cerebellar nuclei of juvenile and adult mice

Abstract

The inferior olive conveys instructive signals to the cerebellum that drive sensorimotor learning. Inferior olivary neurons transmit their signals via climbing fibres, which powerfully excite Purkinje cells, evoking complex spikes and depressing parallel fibre synapses. Additionally, however, these climbing fibres send collaterals to the cerebellar nuclei (CbN). In vivo and in vitro data suggest that climbing fibre collateral excitation is weak in adult mice, raising the question of whether the primary role of this pathway may be developmental. We therefore examined climbing fibre collateral input to large premotor CbN cells over development by virally expressing channelrhodopsin in the inferior olive. In acute cerebellar slices from postnatal day (P)12-14 mice, light-evoked EPSCs were large (> 1 nA at -70 mV). The amplitude of these EPSCs decreased over development, reaching a plateau of ∼350 pA at P20-60. Trains of EPSCs (5 Hz) depressed strongly throughout development, whereas convergence estimates indicated that the total number of functional afferents decreased with age. EPSC waveforms consisted of multiple peaks, probably resulting from action potential bursts in single collaterals and variable times to spike threshold in converging afferents. Activating climbing fibre collaterals evoked well-timed increases in firing probability in CbN neurons, especially in younger mice. The initially strong input, followed by the decrement in synaptic strength coinciding with the pruning of climbing fibres in the cerebellar cortex, implicates the climbing fibre collateral pathway in early postnatal development. Additionally, the persistence of substantial synaptic input at least to P60 suggests that this pathway may function in cerebellar processing into adulthood.

Beta‐gamma burst stimulations of the inferior olive induce high‐frequency oscillations in the deep cerebellar nuclei

“…The sequence was characterised by an initial excitatory response corresponding to the input of the CF collaterals followed by inhibition and rebound. This early evoked response (3.4 ms) fits well with that reported after optogenetic stimulation in vitro (3.3 ms) (Najac & Raman, 2017). Nevertheless, here we observed a stronger excitatory response with two successive excitations before the occurrence of the inhibition and a late rebound.…”

“…The fact that it is possible to enhance associative short‐term plasticity (the synaptically evoked suppression of excitatory PF‐PC synapses, see Brenowitz and Regehr, ) using a short burst stimulation of CF at 400 Hz (Mathy et al ., ) could be seen as an argument in favour of a physiological plausibility of the beta‐gamma stimulation rate. Moreover, the fact the DCN neuron firing rate increased from a baseline of 56 Hz to 269 Hz after optogenetic stimulation of the IO in vitro is in favour of the physiological significance of the 350 Hz oscillation, which can be supported by such increase in the DCN neurons firing rate (Najac & Raman, ).…”

Ocular hypertension drives remodeling of AMPA receptors in select populations of retinal ganglion cells

“…It also provides higher temporal resolution than other approaches, The ChR2-EGFP fusion protein was expressed in type 6 bipolar cell, which provides the majority of input to α On RGCs (Schwartz et al, 2012; Tien et al, 2017), while α Off RGCs appear to receive input from different cohorts of bipolar cells, (Yu et al, 2018) allowing for only a minority of synaptic inputs to be stimulated optogenetically. We examined the relationship between the strength of the stimulus driving ChR2 and the EPSC (Najac and Raman, 2017), and found this relationship to be quite repeatable across cells. One reason for this might be the high degree of convergence of synaptic connections from CB6 input onto individual α On RGCs (Freed et al, 1992; Kerschensteiner et al, 2009; Morgan et al, 2011; Schwartz et al, 2012), allowing for the smoothing of variability in ChR2 expression between bipolar cells.…”

Collateral impact: a dual role for climbing fibre collaterals to the cerebellar nuclei?

“…Initially, each Purkinje cell is innervated by multiple CFs, but only one CF input is strengthened while others are eliminated, so that in the fully developed cerebellum each Purkinje cell is innervated by a single CF (Watanabe & Kano, ). In their recent study, Najac and Raman () investigated CF collateral inputs to the CN during a similar time period and found that CF collaterals provide strong synaptic input to the CN during early development.…”

“…In the first few postnatal weeks, CF collateral inputs to the CN are refined in parallel with CF pruning in the cerebellar cortex. Najac and Raman () estimate that the degree of convergence of CF collaterals on each CN neuron decreases from ∼40 in juvenile mice to ∼8 in adult mice, and it is this reduction in number of inputs that mainly produces the corresponding reduction in synaptic strength in adult animals. This, in turn, may underlie the formation of olivo‐cortico‐nuclear loops, which are widely thought to represent the basic operational units of the adult cerebellum.…”