Purkinje Cell Collaterals Enable Output Signals from the Cerebellar Cortex to Feed Back to Purkinje Cells and Interneurons

Witter, Laurens; Rudolph, Stephanie; Pressler, R. Todd; Lahlaf, Safiya I.; Regehr, Wade G.

doi:10.1016/j.neuron.2016.05.037

Cited by 126 publications

(151 citation statements)

References 48 publications

Supporting

Mentioning

127

Contrasting

Order By: Relevance

“…There was no significant expression in neurons in the forebrain or brainstem. Other neurons in the cerebellum also did not show the fusion protein (see also [37], but see [66]). Three blue LED lights were positioned around the cerebellum of the animal.…”

Section: Resultsmentioning

confidence: 99%

Whole-Cell Properties of Cerebellar Nuclei Neurons In Vivo

2016

Self Cite

View full text Add to dashboard Cite

Cerebellar nuclei neurons integrate sensorimotor information and form the final output of the cerebellum, projecting to premotor brainstem targets. This implies that, in contrast to specialized neurons and interneurons in cortical regions, neurons within the nuclei encode and integrate complex information that is most likely reflected in a large variation of intrinsic membrane properties and integrative capacities of individual neurons. Yet, whether this large variation in properties is reflected in a heterogeneous physiological cell population of cerebellar nuclei neurons with well or poorly defined cell types remains to be determined. Indeed, the cell electrophysiological properties of cerebellar nuclei neurons have been identified in vitro in young rodents, but whether these properties are similar to the in vivo adult situation has not been shown. In this comprehensive study we present and compare the in vivo properties of 144 cerebellar nuclei neurons in adult ketamine-xylazine anesthetized mice. We found regularly firing (N = 88) and spontaneously bursting (N = 56) neurons. Membrane-resistance, capacitance, spike half-width and firing frequency all widely varied as a continuum, ranging from 9.63 to 3352.1 MΩ, from 6.7 to 772.57 pF, from 0.178 to 1.98 ms, and from 0 to 176.6 Hz, respectively. At the same time, several of these parameters were correlated with each other. Capacitance decreased with membrane resistance (R2 = 0.12, P<0.001), intensity of rebound spiking increased with membrane resistance (for 100 ms duration R2 = 0.1503, P = 0.0011), membrane resistance decreased with membrane time constant (R2 = 0.045, P = 0.031) and increased with spike half-width (R2 = 0.023, P<0.001), while capacitance increased with firing frequency (R2 = 0.29, P<0.001). However, classes of neuron subtypes could not be identified using merely k-clustering of their intrinsic firing properties and/or integrative properties following activation of their Purkinje cell input. Instead, using whole-cell parameters in combination with morphological criteria revealed by intracellular labelling with Neurobiotin (N = 18) allowed for electrophysiological identification of larger (29.3–50 μm soma diameter) and smaller (< 21.2 μm) cerebellar nuclei neurons with significant differences in membrane properties. Larger cells had a lower membrane resistance and a shorter spike, with a tendency for higher capacitance. Thus, in general cerebellar nuclei neurons appear to offer a rich and wide continuum of physiological properties that stand in contrast to neurons in most cortical regions such as those of the cerebral and cerebellar cortex, in which different classes of neurons operate in a narrower territory of electrophysiological parameter space. The current dataset will help computational modelers of the cerebellar nuclei to update and improve their cerebellar motor learning and performance models by incorporating the large variation of the in vivo properties of cerebellar nuclei neurons. The cellular complexity of cerebellar nuclei neurons m...

show abstract

Section: Resultsmentioning

confidence: 99%

Whole-Cell Properties of Cerebellar Nuclei Neurons In Vivo

2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…The cerebellar nuclei not only project out of the cerebellum but they also send inhibitory61 and excitatory62 feedback projections to the cerebellar cortex, where they synapse on granule cells and Golgi cells to indirectly affect Purkinje cell function. To counter this circuit, however, potentially destructive abnormal feedback from the cerebellar nuclei in Ptf1a Cre ;Vglut2 fx/fx mice could be dampened by homeostatic control of the Purkinje cells via their own local cortical feedback to granule cells63 or directly to Purkinje cells64. Our awake recordings were intended to capture activity during ongoing and quiet behaviour without distinguishing the Purkinje cell dynamics during motion65 or learning62.…”

Section: Discussionmentioning

confidence: 99%

Genetic silencing of olivocerebellar synapses causes dystonia-like behaviour in mice

2017

View full text Add to dashboard Cite

Theories of cerebellar function place the inferior olive to cerebellum connection at the centre of motor behaviour. One possible implication of this is that disruption of olivocerebellar signalling could play a major role in initiating motor disease. To test this, we devised a mouse genetics approach to silence glutamatergic signalling only at olivocerebellar synapses. The resulting mice had a severe neurological condition that mimicked the early-onset twisting, stiff limbs and tremor that is observed in dystonia, a debilitating movement disease. By blocking olivocerebellar excitatory neurotransmission, we eliminated Purkinje cell complex spikes and induced aberrant cerebellar nuclear activity. Pharmacologically inhibiting the erratic output of the cerebellar nuclei in the mutant mice improved movement. Furthermore, deep brain stimulation directed to the interposed cerebellar nuclei reduced dystonia-like postures in these mice. Collectively, our data uncover a neural mechanism by which olivocerebellar dysfunction promotes motor disease phenotypes and identify the cerebellar nuclei as a therapeutic target for surgical intervention.

show abstract

“…Although synchronized PC firing is not widely observed, synchronized firing by adjacent PCs has been observed in vivo (de Solages et al, 2008). It has been proposed that PC collaterals could allow PCs to synchronize activity in narrow parasagittal bands (de Solages et al, 2008; Witter et al, 2016), making it difficult to detect synchronized PC activity. Frequency-dependent depression, as would occur at most types of synapses, would be expected to diminish strength of PC inputs, and thereby limit the efficacy of PCs to time lock DCN neurons at high frequencies.…”

Section: Discussionmentioning

confidence: 99%

Synaptic Specializations Support Frequency-Independent Purkinje Cell Output from the Cerebellar Cortex

2016

Self Cite

View full text Add to dashboard Cite

Summary The output of the cerebellar cortex is conveyed to the deep cerebellar nuclei (DCN) by Purkinje cells (PCs). Here we characterize the properties of the PC-DCN synapse in juvenile and adult mice and find that prolonged high-frequency stimulation leads to steady-state responses that become increasingly frequency-independent within the physiological firing range of PCs in older animals, resulting in a linear relationship between charge transfer and activation frequency. We use a low affinity antagonist to show that GABAA receptor saturation occurs at this synapse, but it does not underlie frequency invariant transmission. We propose that PC-DCN synapses have two components of release: one prominent early in trains, and another specialized to maintain transmission during prolonged activation. Short-term facilitation offsets partial vesicle depletion to produce frequency-independent transmission.

show abstract

Purkinje Cell Collaterals Enable Output Signals from the Cerebellar Cortex to Feed Back to Purkinje Cells and Interneurons

Cited by 126 publications

References 48 publications

Whole-Cell Properties of Cerebellar Nuclei Neurons In Vivo

Whole-Cell Properties of Cerebellar Nuclei Neurons In Vivo

Genetic silencing of olivocerebellar synapses causes dystonia-like behaviour in mice

Synaptic Specializations Support Frequency-Independent Purkinje Cell Output from the Cerebellar Cortex

Contact Info

Product

Resources

About