Hyperpolarization Induces a Long-Term Increase in the Spontaneous Firing Rate of Cerebellar Golgi Cells

Golgi cells (GoCs) are inhibitory interneurons that influence the cerebellar cortical response to sensory input by regulating the excitability of the granule cell layer. While GoC inhibition is essential for normal motor coordination, little is known about the circuit dynamics that govern the activity of these cells. In particular, although GoC spontaneous spiking influences the extent of inhibition and gain throughout the granule cell layer, it is not known whether this spontaneous activity can be modulated in a long-term manner. Here we describe a form of long-term plasticity that regulates the spontaneous firing rate of GoCs in the rat cerebellar cortex. We find that membrane hyperpolarization, either by mGluR2 activation of potassium channels, or by somatic current injection, induces a long-lasting increase in GoC spontaneous firing. This spike rate plasticity appears to result from a strong reduction in the spike after hyperpolarization. Pharmacological manipulations suggest the involvement of calcium-calmodulin-dependent kinase II and calcium-activated potassium channels in mediating these firing rate increases. As a consequence of this plasticity, GoC spontaneous spiking is selectively enhanced, but the gain of evoked spiking is unaffected. Hence, this plasticity is well suited for selectively regulating the tonic output of GoCs rather than their sensory-evoked responses.

[1]  Tiago Branco,et al.  Tonic Inhibition Enhances Fidelity of Sensory Information Transmission in the Cerebellar Cortex , 2012, The Journal of Neuroscience.

[2]  Court Hull,et al.  Identification of an Inhibitory Circuit that Regulates Cerebellar Golgi Cell Activity , 2012, Neuron.

[3]  R. A. Hensbroek,et al.  Spontaneous Activity Signatures of Morphologically Identified Interneurons in the Vestibulocerebellum , 2011, The Journal of Neuroscience.

[4]  R. Silver,et al.  Rapid Desynchronization of an Electrically Coupled Interneuron Network with Sparse Excitatory Synaptic Input , 2010, Neuron.

[5]  Wei Xu,et al.  Cerebellar Golgi cells in the rat receive convergent peripheral inputs via a lateral reticular nucleus relay , 2010, The European journal of neuroscience.

[6]  G. Cheron,et al.  BK Channels Control Cerebellar Purkinje and Golgi Cell Rhythmicity In Vivo , 2009, PloS one.

[7]  Wade G. Regehr,et al.  Dynamics of Fast and Slow Inhibition from Cerebellar Golgi Cells Allow Flexible Control of Synaptic Integration , 2009, Neuron.

[8]  Seok-Jin R. Lee,et al.  Activation of CaMKII in single dendritic spines during long-term potentiation , 2009, Nature.

[9]  S. D. Lac,et al.  Frequency-Independent Synaptic Transmission Supports a Linear Vestibular Behavior , 2008, Neuron.

[10]  Egidio D'Angelo,et al.  Ionic mechanisms of autorhythmic firing in rat cerebellar Golgi cells , 2006, The Journal of physiology.

[11]  Tahl Holtzman,et al.  Different responses of rat cerebellar Purkinje cells and Golgi cells evoked by widespread convergent sensory inputs , 2006, The Journal of physiology.

[12]  Masao Ito.  Cerebellar circuitry as a neuronal machine , 2006, Progress in Neurobiology.

[13]  Robert Brenner,et al.  BK channel β4 subunit reduces dentate gyrus excitability and protects against temporal lobe seizures , 2005, Nature Neuroscience.

[14]  Aryn H. Gittis,et al.  Decreases in CaMKII Activity Trigger Persistent Potentiation of Intrinsic Excitability in Spontaneously Firing Vestibular Nucleus Neurons , 2005, Neuron.

[15]  M. Häusser,et al.  Integration of quanta in cerebellar granule cells during sensory processing , 2004, Nature.

[16]  C. Sekirnjak,et al.  Long-Lasting Increases in Intrinsic Excitability Triggered by Inhibition , 2003, Neuron.

[17]  Dai Watanabe,et al.  mGluR2 Postsynaptically Senses Granule Cell Inputs at Golgi Cell Synapses , 2003, Neuron.

[18]  R. Silver,et al.  Shunting Inhibition Modulates Neuronal Gain during Synaptic Excitation , 2003, Neuron.

[19]  David Attwell,et al.  Tonic and Spillover Inhibition of Granule Cells Control Information Flow through Cerebellar Cortex , 2002, Neuron.

[20]  R. Angus Silver,et al.  GABA Spillover from Single Inhibitory Axons Suppresses Low-Frequency Excitatory Transmission at the Cerebellar Glomerulus , 2000, The Journal of Neuroscience.

[21]  K. Toyama,et al.  Ablation of Cerebellar Golgi Cells Disrupts Synaptic Integration Involving GABA Inhibition and NMDA Receptor Activation in Motor Coordination , 1998, Cell.

[22]  L. Toro,et al.  Large conductance voltage- and calcium-dependent K+ channel, a distinct member of voltage-dependent ion channels with seven N-terminal transmembrane segments (S0-S6), an extracellular N terminus, and an intracellular (S9-S10) C terminus. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[23]  S. Cull-Candy,et al.  Development of a tonic form of synaptic inhibition in rat cerebellar granule cells resulting from persistent activation of GABAA receptors. , 1996, The Journal of physiology.

[24]  T. Kaneko,et al.  Immunohistochemical localization of metabotropic glutamate receptors, mGluR2 and mGluR3, in rat cerebellar cortex , 1994, Neuron.

[25]  J. Eccles,et al.  Golgi Cell Inhibition in the Cerebellar Cortex , 1964, Nature.

[26]  S. du Lac,et al.  Bidirectional control of BK channel open probability by CAMKII and PKC in medial vestibular nucleus neurons. , 2011, Journal of neurophysiology.

[27]  B. Connors,et al.  Functional properties of electrical synapses between inhibitory interneurons of neocortical layer 4. , 2005, Journal of neurophysiology.

[28]  Professor Dr. John C. Eccles,et al.  The Cerebellum as a Neuronal Machine , 1967, Springer Berlin Heidelberg.

[29]  Supplemental Data Supplemental Experimental Procedures Slices preparation , 2022 .