Cerebellar Inhibitory Input to the Inferior Olive Decreases Electrical Coupling and Blocks Subthreshold Oscillations

Lefler, Yaara; Yarom, Yosef; Uusisaari, Marylka Yoe

doi:10.1016/j.neuron.2014.02.032

Cited by 120 publications

(147 citation statements)

References 76 publications

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“…We do not know the source of this extra synchrony or the mechanisms that modulate it during sensory stimulation. However, we note that electrical coupling of cells in the inferior olive (IO) plays an important role in synchronizing CF activity (De Zeeuw et al, 1997; Blenkinsop and Lang, 2006; Van Der Giessen et al, 2008), and that the coupling coefficient can be dynamically modulated up and down via stimulus-related activation of synaptic inputs to the IO (Llinás and Sasaki, 1989; Lang, 2002; Lefler et al, 2014; De Gruijl et al, 2014b). …”

Section: Discussionmentioning

confidence: 99%

Coding of stimulus strength via analog calcium signals in Purkinje cell dendrites of awake mice

Najafi

Giovannucci

Wang

et al. 2014

eLife

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The climbing fiber input to Purkinje cells acts as a teaching signal by triggering a massive influx of dendritic calcium that marks the occurrence of instructive stimuli during cerebellar learning. Here, we challenge the view that these calcium spikes are all-or-none and only signal whether the instructive stimulus has occurred, without providing parametric information about its features. We imaged ensembles of Purkinje cell dendrites in awake mice and measured their calcium responses to periocular airpuffs that serve as instructive stimuli during cerebellar-dependent eyeblink conditioning. Information about airpuff duration and pressure was encoded probabilistically across repeated trials, and in two additional signals in single trials: the synchrony of calcium spikes in the Purkinje cell population, and the amplitude of the calcium spikes, which was modulated by a non-climbing fiber pathway. These results indicate that calcium-based teaching signals in Purkinje cells contain analog information that encodes the strength of instructive stimuli trial-by-trial.DOI: http://dx.doi.org/10.7554/eLife.03663.001

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Section: Discussionmentioning

confidence: 99%

Coding of stimulus strength via analog calcium signals in Purkinje cell dendrites of awake mice

Najafi

Giovannucci

Wang

et al. 2014

eLife

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“…In the IO, these membrane potential oscillations are thought to rely on interactions between neurons connected by gap junctions. The properties of these gap junctions, and hence the interactions between neurons in the IO, in turn depend on activation of glutamatergic NMDA receptors (Mathy et al, 2014), as well as GABAergic input from the CN (Lefler et al, 2014). We observed oscillations in simple and complex spike activity in 5 of 12 cells after the CS (Figure 7).…”

Section: Discussionmentioning

confidence: 99%

Changes in complex spike activity during classical conditioning

Rasmussen

Jirenhed

Wetmore

et al. 2014

Front. Neural Circuits

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The cerebellar cortex is necessary for adaptively timed conditioned responses (CRs) in eyeblink conditioning. During conditioning, Purkinje cells acquire pause responses or “Purkinje cell CRs” to the conditioned stimuli (CS), resulting in disinhibition of the cerebellar nuclei (CN), allowing them to activate motor nuclei that control eyeblinks. This disinhibition also causes inhibition of the inferior olive (IO), via the nucleo-olivary pathway (N-O). Activation of the IO, which relays the unconditional stimulus (US) to the cortex, elicits characteristic complex spikes in Purkinje cells. Although Purkinje cell activity, as well as stimulation of the CN, is known to influence IO activity, much remains to be learned about the way that learned changes in simple spike firing affects the IO. In the present study, we analyzed changes in simple and complex spike firing, in extracellular Purkinje cell records, from the C3 zone, in decerebrate ferrets undergoing training in a conditioning paradigm. In agreement with the N-O feedback hypothesis, acquisition resulted in a gradual decrease in complex spike activity during the conditioned stimulus, with a delay that is consistent with the long N-O latency. Also supporting the feedback hypothesis, training with a short interstimulus interval (ISI), which does not lead to acquisition of a Purkinje cell CR, did not cause a suppression of complex spike activity. In contrast, observations that extinction did not lead to a recovery in complex spike activity and the irregular patterns of simple and complex spike activity after the conditioned stimulus are less conclusive.

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“…Finally, Lefler et al [••39] have recently examined the mechanism through which GABAergic projections from the deep cerebellar nuclei (DCN) transiently decouple IO neurons. The arrangement of IO dendritic spines in glomeruli containing electrical synapses surrounded by inhibitory and excitatory terminals (Figure 4) prompted Llinas to propose 40 years ago that synaptic activation could transiently decouple IO neurons through shunting inhibition [40].…”

Section: Timing Is Everythingmentioning

confidence: 99%

“…The arrangement of IO dendritic spines in glomeruli containing electrical synapses surrounded by inhibitory and excitatory terminals (Figure 4) prompted Llinas to propose 40 years ago that synaptic activation could transiently decouple IO neurons through shunting inhibition [40]. Lefler et al [••39] tested this hypothesis using optogenetic stimulation of GABAergic neurons from the DCN that project to the IO. Light pulses produced inhibitory currents in IO neurons with slow time courses, which merged into steady sustained inhibitory currents during trains of pulses.…”

Section: Timing Is Everythingmentioning

confidence: 99%

The ever-changing electrical synapse

O’Brien

2014

Current Opinion in Neurobiology

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A wealth of research has revealed that electrical synapses in the central nervous system exhibit a high degree of plasticity. Several recent studies, particularly in the retina and inferior olive, highlight this plasticity. Three classes of mechanisms can alter electrical coupling over time courses ranging from milliseconds to days. Changes of membrane conductance through synaptic input or spiking activity shunt current and decouple neurons on the millisecond time scale. Such activity can also alter coupling symmetry, rectifying electrical synapses. More stable rectification can be accomplished through molecular asymmetry of the synapse itself. On the minutes time scale, changes in connexin phosphorylation can change coupling quasi-stably with order of magnitude dynamic range. On the hours to days time scale, changes in expression level of connexins alter coupling through the course of circadian time, over developmental time, or in response to tissue injury. Combined, all of these mechanisms allow electrical coupling to be highly dynamic, changing in response to demands at the whole network level, in small portions of a network, or at the level of an individual synapse.

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Cerebellar Inhibitory Input to the Inferior Olive Decreases Electrical Coupling and Blocks Subthreshold Oscillations

Cited by 120 publications

References 76 publications

Coding of stimulus strength via analog calcium signals in Purkinje cell dendrites of awake mice

Coding of stimulus strength via analog calcium signals in Purkinje cell dendrites of awake mice

Changes in complex spike activity during classical conditioning

The ever-changing electrical synapse

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