Questioning the role of rebound firing in the cerebellum

Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Nature Neuroscience (Impact Factor: 16.1). 10/2008; 11(11):1256-8. DOI: 10.1038/nn.2195
Source: PubMed


A key component of recent theories on cerebellar function is rebound firing in neurons of the deep cerebellar nuclei (DCN). Despite the robustness of this phenomenon in vitro, in vivo studies have provided little evidence for its prevalence. We found that intact mouse or rat DCN neurons rarely showed rebound firing under physiological conditions in vitro or in vivo. These observations necessitate a critical re-evaluation of recent cerebellar models.

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    • "They observed a short burst of DCN cells after current-induced hyperpolarization or synchronous activation of a large number of PCs. However, there are vigorous discussions about whether the conditions required for rebound excitation are realistic in physiological conditions, especially in behaving animals [15], [16], [17], [18], [19], [20]. Second, suppression of PC activity could generate burst activity of DCN cells by disinhibition, as suggested by previous studies [13], [21], [22], [23], [24]. "
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    ABSTRACT: The cerebellum generates its vast amount of output to the cerebral cortex through the dentate nucleus (DN) that is essential for precise limb movements in primates. Nuclear cells in DN generate burst activity prior to limb movement, and inactivation of DN results in cerebellar ataxia. The question is how DN cells become active under intensive inhibitory drive from Purkinje cells (PCs). There are two excitatory inputs to DN, mossy fiber and climbing fiber collaterals, but neither of them appears to have sufficient strength for generation of burst activity in DN. Therefore, we can assume two possible mechanisms: post-inhibitory rebound excitation and disinhibition. If rebound excitation works, phasic excitation of PCs and a concomitant inhibition of DN cells should precede the excitation of DN cells. On the other hand, if disinhibition plays a primary role, phasic suppression of PCs and activation of DN cells should be observed at the same timing. To examine these two hypotheses, we compared the activity patterns of PCs in the cerebrocerebellum and DN cells during step-tracking wrist movements in three Japanese monkeys. As a result, we found that the majority of wrist-movement-related PCs were suppressed prior to movement onset and the majority of wrist-movement-related DN cells showed concurrent burst activity without prior suppression. In a minority of PCs and DN cells, movement-related increases and decreases in activity, respectively, developed later. These activity patterns suggest that the initial burst activity in DN cells is generated by reduced inhibition from PCs, i.e., by disinhibition. Our results indicate that suppression of PCs, which has been considered secondary to facilitation, plays the primary role in generating outputs from DN. Our findings provide a new perspective on the mechanisms used by PCs to influence limb motor control and on the plastic changes that underlie motor learning in the cerebrocerebellum.
    PLoS ONE 10/2014; 9(10):e108774. DOI:10.1371/journal.pone.0108774 · 3.23 Impact Factor
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    • "Recent studies of deep cerebellar nuclear (DCN) neurons have focused exclusively on the integration of inhibitory Purkinje cell input and the postinhibitory rebound excitation [1]–[4]. But the primary response mode of DNC neurons under behavior is excitatory modulation that arise without any substantial preceding inhibition [5]–[8], and which are therefore likely to be a least partly driven by the mossy fiber (MF) inputs to DCN neurons. "
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    ABSTRACT: Many mossy fiber pathways to the neurons of the deep cerebellar nucleus (DCN) originate from the spinal motor circuitry. For cutaneously activated spinal neurons, the receptive field is a tag indicating the specific motor function the spinal neuron has. Similarly, the climbing fiber receptive field of the DCN neuron reflects the specific motor output function of the DCN neuron. To explore the relationship between the motor information the DCN neuron receives and the output it issues, we made patch clamp recordings of DCN cell responses to tactile skin stimulation in the forelimb region of the anterior interposed nucleus in vivo. The excitatory responses were organized according to a general principle, in which the DCN cell responses became stronger the closer the skin site was located to its climbing fiber receptive field. The findings represent a novel functional principle of cerebellar connectivity, with crucial importance for our understanding of the function of the cerebellum in movement coordination.
    PLoS ONE 01/2014; 9(1):e84616. DOI:10.1371/journal.pone.0084616 · 3.23 Impact Factor
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    • "The neural coding strategies used by DCN cells are still being determined, but extensive work in vitro has established that they have the capacity to respond to inhibition with a rebound increase in firing rate (Jahnsen, 1986a; Aizenman and Linden , 1999; Molineux et al., 2006, 2008; Tadayonnejad et al., 2009, 2010; Hoebeek et al., 2010; Sangrey and Jaeger, 2010; Engbers et al., 2011). The extent to which this occurs in response to physiological stimuli has recently been debated (Alvina et al., 2008; Person and Raman, 2012), although some consensus begins to emerge from both in vivo and in vitro work that DCN cells can exhibit a rebound increase in firing frequency given a significantly large inhibitory input that could arise in relation to the frequency, number, and in particular, synchronous input from Purkinje cells (Aizenman and Linden, 1999; Zhang et al., 2004; Wetmore et al., 2008; Tadayonnejad et al., 2009, 2010; Hoebeek et al., 2010; Bengtsson et al., 2011). Nevertheless, the ionic mechanisms that could facilitate a rebound response are still under investigation. "
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    ABSTRACT: T-type calcium channels of the Cav3 family are unique among voltage-gated calcium channels due to their low activation voltage, rapid inactivation, and small single channel conductance. These special properties allow Cav3 calcium channels to regulate neuronal processing in the subthreshold voltage range. Here, we review two different subthreshold ion channel interactions involving Cav3 channels and explore the ability of these interactions to expand the functional roles of Cav3 channels. In cerebellar Purkinje cells, Cav3 and intermediate conductance calcium-activated potassium (IKCa) channels form a novel complex which creates a low voltage-activated, transient outward current capable of suppressing temporal summation of excitatory postsynaptic potentials (EPSPs). In large diameter neurons of the deep cerebellar nuclei, Cav3-mediated calcium current (IT) and hyperpolarization-activated cation current (IH) are activated during trains of IPSPs. These currents have distinct, and yet synergistic, roles in the subthreshold domain with IT generating a rebound burst and IH controlling first spike latency and rebound spike precision. However, by shortening the membrane time constant the membrane returns towards resting value at a faster rate, allowing IH to increase the efficacy of IT, and increase the range of burst frequencies that can be generated. The net effect of Cav3 channels thus depends on the channels with which they are paired. When expressed in a complex with a KCa channel, Cav3 channels reduce excitability when processing excitatory inputs. If functionally coupled with an HCN channel, the depolarizing effect of Cav3 channels is accentuated, allowing for efficient inversion of inhibitory inputs to generate a rebound burst output. Therefore, signal processing relies not only on the activity of individual subtypes of channels but also on complex interactions between ion channels whether based on a physical complex or by indirect effects on membrane properties.
    Frontiers in Cellular Neuroscience 11/2013; 7:230. DOI:10.3389/fncel.2013.00230 · 4.29 Impact Factor
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