Review
Nothing can be coincidence: synaptic inhibition and plasticity in the cerebellar nuclei

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Many cerebellar neurons fire spontaneously, generating 10–100 action potentials per second even without synaptic input. This high basal activity correlates with information-coding mechanisms that differ from those of cells that are quiescent until excited synaptically. For example, in the deep cerebellar nuclei, Hebbian patterns of coincident synaptic excitation and postsynaptic firing fail to induce long-term increases in the strength of excitatory inputs. Instead, excitatory synaptic currents are potentiated by combinations of inhibition and excitation that resemble the activity of Purkinje and mossy fiber afferents that is predicted to occur during cerebellar associative learning tasks. Such results indicate that circuits with intrinsically active neurons have rules for information transfer and storage that distinguish them from other brain regions.

Introduction

Neurons and synapses throughout the vertebrate brain share many common properties, which have given rise to the useful generalizations taught in introductory neuroscience courses: neurons rest near −65 mV; voltage-gated Na+ channels inactivate after opening; depletion of a presynaptic neurotransmitter produces synaptic depression; and long-term potentiation (LTP) results from coincident presynaptic glutamate release and postsynaptic depolarization. Current research, however, is revealing the diversity of electrical and chemical signaling mechanisms employed by neurons in different brain regions. One such area is the cerebellum, particularly regarding signaling from Purkinje neurons to their target neurons in the medial, interpositus and lateral cerebellar nuclei. Purkinje neurons, located in the cerebellar cortex, are among the most studied cells in the vertebrate brain. By contrast, despite being the oblique referent of the frequently quoted statements that Purkinje neurons ‘are the sole output of the cerebellar cortex’ and ‘exert a powerful inhibitory control on their targets’, cerebellar nuclear neurons have been the focus of far fewer studies, and exploration of their properties at the cellular level is only beginning to become widespread. Recent work has demonstrated that these neurons and the synapses onto them provide an exception to all the generalizations just mentioned. These deviations from the norm are interesting, not only because they demand that we re-examine the bases for common assumptions but also because they reveal mechanisms underlying specific, well-characterized forms of cerebellar learning.

Section snippets

Spontaneous firing in cerebellar neurons

Neither Purkinje neurons nor cerebellar nuclear cells have a true resting potential. Instead, both cell types are active in the basal state, firing tens of action potentials per second in vivo when animals are not engaged in cerebellar behaviors 1, 2. This activity is intrinsically generated: the neurons continue to fire spontaneously in vitro even in the absence of synaptic input 3, 4, 5, 6, 7, 8, 9. This high level of basal activity keeps the firing rates of the neurons in the middle of their

Minimizing inhibitory synaptic depression in spontaneously firing neurons

During cerebellar behaviors, increased activity in Purkinje neurons can and does suppress firing by nuclear neurons 21, 22. Studies in cerebellar slice preparations indicate that silencing of nuclear cells requires a consistent inhibitory shunt, which might be achieved when Purkinje cell afferents fire coherently and/or at rates exceeding the basal level. Conversely, any lapse of the inhibitory conductance leads to the resumption of firing 22, 23, 24.

The constant basal and driven activity of

Rebound bursts of cerebellar nuclear cells

A much-explored feature of nuclear cells is their tendency to fire action potentials after periods of hyperpolarization 8, 28, 29. These ‘rebound spikes’ often consist of a short series of action potentials produced at a higher rate than those occurring before the hyperpolarization. Alternatively, they sometimes form a true burst of high-frequency action potentials. Although the ionic mechanisms underlying the accelerated firing or the true burst are likely to differ, in both cases the rebound

Information coding in cerebellar circuits

The question of how information is encoded in a circuit with substantial ongoing activity has been approached in many ways, starting with an analysis of the anatomy of cerebellar circuits and the ‘sign’ of synaptic transmission. Purkinje neurons, nuclear neurons and inferior olivary neurons in the brainstem form a trisynaptic, functionally inhibitory loop with the activity of Purkinje and nuclear neurons modulated by excitatory mossy fiber afferents 43, 44 (Figure 3a). Specifically,

Coincidence detection in spontaneously active neurons

This hypothesis (the Medina-Mauk model) raises the question of how inhibition might generate a signal detected by excitatory synapses and, more generally, what synaptic, spike-related and biochemical events can trigger a long-lasting modulation of cerebellar output. In other brain regions, LTP of excitatory synaptic responses results from coincidence detection of signals that, together, permit a substantial Ca2+ influx. Perhaps the best studied example is provided by CA1 hippocampal pyramidal

Synaptic plasticity at mossy fiber synapses onto nuclear cells

This possibility was tested by recording EPSCs from nuclear cells in mouse cerebellar slices before and after application of a variety of combinations of excitatory and inhibitory stimuli [64]. The putative induction protocols included a high-frequency train of EPSPs evoked by stimulation of mossy fibers, with or without a period of hyperpolarization (induced by current injection) followed by rebound spiking. Consistent with the Medina-Mauk model of cerebellar learning, trains of

Relating cellular plasticity to behavioral studies

The effective induction protocols in the cerebellar nuclei conform in many respects to predicted patterns of excitation and inhibition predicted to take place during cerebellar learning. First, plasticity is synapse specific [67], consistent with the lack of stimulus generalization of conditioned responses in rabbits, even after cerebellar cortical control is eliminated [71]. Second, synaptic excitation must occur in a specific time window to induce potentiation, preceding the hyperpolarization

Concluding remarks

The cellular characteristics of cerebellar nuclear neurons are distinct from those of many other principal cells. They fire spontaneously by seeking a suprathreshold resting potential, and the basal activity of a multitude of Purkinje afferents makes Cl influx through GABAA receptors act as a virtual intrinsic current that keeps nuclear cells in the middle of their dynamic range. The non-Hebbian rules for potentiation of EPSCs in cerebellar nuclear neurons, which require synaptic excitation

Acknowledgements

Supported by the National Institutes of Health (www.nih.gov) NIH-NS39395 (I.M.R.). Studies of synaptic plasticity that form the focus of this review were also supported by F31-NS055542 (J.R.P.). We acknowledge members of the Raman laboratory who participated in the work from the laboratory cited in the review, Amy Gustafson, Dan Padgett, Petra Telgkamp, Tina Grieco, Zayd Khaliq and Teresa Aman, in addition to current laboratory members Nan Zheng, Abigail Person, Jason Bant and Mark Benton for

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