Electrical Coupling Mediates Tunable Low-Frequency Oscillations and Resonance in the Cerebellar Golgi Cell Network

Tonic motor control involves oscillatory synchronization of activity at low frequency (5-30 Hz) throughout the sensorimotor system, including cerebellar areas. We investigated the mechanisms underpinning cerebellar oscillations. We found that Golgi interneurons, which gate information transfer in the cerebellar cortex input layer, are extensively coupled through electrical synapses. When depolarized in vitro, these neurons displayed low-frequency oscillatory synchronization, imposing rhythmic inhibition onto granule cells. Combining experiments and modeling, we show that electrical transmission of the spike afterhyperpolarization is the essential component for oscillatory population synchronization. Rhythmic firing arises in spite of strong heterogeneities, is frequency tuned by the mean excitatory input to Golgi cells, and displays pronounced resonance when the modeled network is driven by oscillating inputs. In vivo, unitary Golgi cell activity was found to synchronize with low-frequency LFP oscillations occurring during quiet waking. These results suggest a major role for Golgi cells in coordinating cerebellar sensorimotor integration during oscillatory interactions.

[1]  T. Sejnowski,et al.  Network Oscillations: Emerging Computational Principles , 2006, The Journal of Neuroscience.

[2]  Freek E. Hoebeek,et al.  Causes and Consequences of Oscillations in the Cerebellar Cortex , 2008, Neuron.

[3]  P. Somogyi,et al.  Colocalization of glycine-like and GABA-like immunoreactivities in Golgi cell terminals in the rat cerebellum: a postembedding light and electron microscopic study , 1988, Brain Research.

[4]  Y Yarom,et al.  Electrotonic Coupling Interacts with Intrinsic Properties to Generate Synchronized Activity in Cerebellar Networks of Inhibitory Interneurons , 1999, The Journal of Neuroscience.

[5]  Germán Mato,et al.  Electrical Synapses and Synchrony: The Role of Intrinsic Currents , 2003, The Journal of Neuroscience.

[6]  T. Sejnowski,et al.  Correlated neuronal activity and the flow of neural information , 2001, Nature Reviews Neuroscience.

[7]  Xiao-Jing Wang,et al.  What determines the frequency of fast network oscillations with irregular neural discharges? I. Synaptic dynamics and excitation-inhibition balance. , 2003, Journal of neurophysiology.

[8]  J. Fritschy,et al.  Heterogeneity of glycinergic and gabaergic interneurons in the granule cell layer of mouse cerebellum , 2007, The Journal of comparative neurology.

[9]  John P Welsh,et al.  Continuous Electrical Oscillations Emerge from a Coupled Network: A Study of the Inferior Olive using Lentiviral Knockdown of Connexin36 , 2006, The Journal of Neuroscience.

[10]  Hanns Ulrich Zeilhofer,et al.  Glycinergic neurons expressing enhanced green fluorescent protein in bacterial artificial chromosome transgenic mice , 2005, The Journal of comparative neurology.

[11]  S. Dieudonné,et al.  IPSC Kinetics at Identified GABAergic and Mixed GABAergic and Glycinergic Synapses onto Cerebellar Golgi Cells , 2001, The Journal of Neuroscience.

[12]  Chris I. De Zeeuw,et al.  Time windows and reverberating loops: a reverse-engineering approach to cerebellar function , 2008, The Cerebellum.

[13]  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.

[14]  D. Rossi,et al.  Spillover-Mediated Transmission at Inhibitory Synapses Promoted by High Affinity α6 Subunit GABAA Receptors and Glomerular Geometry , 1998, Neuron.

[15]  N. Belluardo,et al.  Expression of Connexin36 in the adult and developing rat brain 1 1 Published on the World Wide Web on 12 April 2000. , 2000, Brain Research.

[16]  M. Steriade,et al.  The reticular nucleus revisited: Intrinsic and network properties of a thalamic pacemaker , 2005, Progress in Neurobiology.

[17]  D. Kleinfeld,et al.  Coherent electrical activity between vibrissa sensory areas of cerebellum and neocortex is enhanced during free whisking. , 2002, Journal of neurophysiology.

[18]  Anna Devor,et al.  Deformation of Network Connectivity in the Inferior Olive of Connexin 36-Deficient Mice Is Compensated by Morphological and Electrophysiological Changes at the Single Neuron Level , 2003, The Journal of Neuroscience.

[19]  R Angus Silver,et al.  Synaptic and Cellular Properties of the Feedforward Inhibitory Circuit within the Input Layer of the Cerebellar Cortex , 2008, The Journal of Neuroscience.

[20]  F. Cicirata,et al.  Expression of pannexin1 in the CNS of adult mouse: Cellular localization and effect of 4-aminopyridine-induced seizures , 2006, Neuroscience.

[21]  A. Marty,et al.  Developmental Changes in Parvalbumin Regulate Presynaptic Ca2+ Signaling , 2005, The Journal of Neuroscience.

[22]  S. Bloomfield,et al.  Gap junctional coupling underlies the short-latency spike synchrony of retinal alpha ganglion cells. , 2003, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[23]  S. Dieudonné,et al.  Submillisecond kinetics and low efficacy of parallel fibre‐Golgi cell synaptic currents in the rat cerebellum , 1998, The Journal of physiology.

[24]  C. Mulle,et al.  Kainate receptor-mediated synaptic currents in cerebellar Golgi cells are not shaped by diffusion of glutamate. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[25]  S. Bloomfield,et al.  Gap Junctional Coupling Underlies the Short-Latency Spike Synchrony of Retinal α Ganglion Cells , 2003, The Journal of Neuroscience.

[26]  E De Schutter,et al.  The function of cerebellar Golgi cells revisited. , 2000, Progress in brain research.

[27]  Nicolas Brunel,et al.  High-Frequency Organization and Synchrony of Activity in the Purkinje Cell Layer of the Cerebellum , 2008, Neuron.

[28]  Bard Ermentrout,et al.  When inhibition not excitation synchronizes neural firing , 1994, Journal of Computational Neuroscience.

[29]  Carson C. Chow,et al.  Dynamics of Spiking Neurons with Electrical Coupling , 2000, Neural Computation.

[30]  V Taglietti,et al.  Theta-Frequency Bursting and Resonance in Cerebellar Granule Cells: Experimental Evidence and Modeling of a Slow K+-Dependent Mechanism , 2001, The Journal of Neuroscience.

[31]  E. De Schutter,et al.  Resonant Synchronization in Heterogeneous Networks of Inhibitory Neurons , 2003, The Journal of Neuroscience.

[32]  David Golomb,et al.  The Combined Effects of Inhibitory and Electrical Synapses in Synchrony , 2005, Neural Computation.

[33]  P. Wahle,et al.  Pannexin expression in the cerebellum , 2008, The Cerebellum.

[34]  S. Hestrin,et al.  Electrical Coupling among Irregular-Spiking GABAergic Interneurons Expressing Cannabinoid Receptors , 2004, The Journal of Neuroscience.

[35]  R. Hari,et al.  Synchronous cortical oscillatory activity during motor action , 2003, Current Opinion in Neurobiology.

[36]  E. De Schutter,et al.  Synchronization of golgi and granule cell firing in a detailed network model of the cerebellar granule cell layer. , 1998, Journal of neurophysiology.

[37]  B. Connors,et al.  Two networks of electrically coupled inhibitory neurons in neocortex , 1999, Nature.

[38]  Yves Lamarre,et al.  Local field potential oscillations in primate cerebellar cortex: modulation during active and passive expectancy. , 2002, Journal of neurophysiology.

[39]  M. Mauk,et al.  Cerebellar function: Coordination, learning or timing? , 2000, Current Biology.

[40]  Yves Lamarre,et al.  Local field potential oscillations in primate cerebellar cortex: synchronization with cerebral cortex during active and passive expectancy. , 2005, Journal of neurophysiology.

[41]  John Rinzel,et al.  Synchronization of Electrically Coupled Pairs of Inhibitory Interneurons in Neocortex , 2007, The Journal of Neuroscience.

[42]  B. Connors,et al.  Synchronous Activity of Inhibitory Networks in Neocortex Requires Electrical Synapses Containing Connexin36 , 2001, Neuron.

[43]  Kanichay Rt,et al.  Synaptic and Cellular Properties of the Feedforward Inhibitory Circuit within the Input Layer of the Cerebellar Cortex , 2008 .

[44]  P. Wahle,et al.  Site‐specific and developmental expression of pannexin1 in the mouse nervous system , 2005, The European journal of neuroscience.

[45]  P. Jonas,et al.  Shunting Inhibition Improves Robustness of Gamma Oscillations in Hippocampal Interneuron Networks by Homogenizing Firing Rates , 2006, Neuron.

[46]  M. Whittington,et al.  A Novel Network of Multipolar Bursting Interneurons Generates Theta Frequency Oscillations in Neocortex , 2003, Neuron.

[47]  Charles M. Gray,et al.  Synchronous oscillations in neuronal systems: Mechanisms and functions , 1994, Journal of Computational Neuroscience.

[48]  J. Nadal,et al.  Optimal Information Storage and the Distribution of Synaptic Weights Perceptron versus Purkinje Cell , 2004, Neuron.

[49]  A. Schnitzler,et al.  Normal and pathological oscillatory communication in the brain , 2005, Nature Reviews Neuroscience.

[50]  D. Marr.  A theory of cerebellar cortex , 1969, The Journal of physiology.

[51]  R. Llinás,et al.  Role of gap junctions in synchronized neuronal oscillations in the inferior olive. , 2005, Journal of neurophysiology.

[52]  Henrik Jörntell,et al.  Properties of Somatosensory Synaptic Integration in Cerebellar Granule Cells In Vivo , 2006, The Journal of Neuroscience.

[53]  Y. Lamarre,et al.  Local field potential oscillations in primate cerebellar cortex during voluntary movement. , 1997, Journal of neurophysiology.

[54]  R. Llinás,et al.  In vivo mouse inferior olive neurons exhibit heterogeneous subthreshold oscillations and spiking patterns , 2007, Proceedings of the National Academy of Sciences.

[55]  S. Baker,et al.  Cortico-cerebellar coherence during a precision grip task in the monkey. , 2006, Journal of neurophysiology.

[56]  Erik De Schutter,et al.  Parallel Fibers Synchronize Spontaneous Activity in Cerebellar Golgi Cells , 1999, The Journal of Neuroscience.

[57]  J. Albus.  A Theory of Cerebellar Function , 1971 .

[58]  H. Monyer,et al.  Pannexin1 and Pannexin2 expression in the developing and mature rat brain. , 2005, Brain research. Molecular brain research.

[59]  B. Ermentrout,et al.  Chemical and electrical synapses perform complementary roles in the synchronization of interneuronal networks. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[60]  G. Deuschl,et al.  Pathophysiology of nonparkinsonian tremors , 2002, Movement disorders : official journal of the Movement Disorder Society.

[61]  N. Belluardo,et al.  Expression of Cx36 in mammalian neurons , 2000, Brain Research Reviews.

[62]  G. Buzsáki,et al.  Gamma Oscillation by Synaptic Inhibition in a Hippocampal Interneuronal Network Model , 1996, The Journal of Neuroscience.

[63]  P. Fortier,et al.  Estimating conductances of dual-recorded neurons within a network of coupled cells. , 2006, Journal of theoretical biology.

[64]  E. M. Pinches,et al.  The role of synchrony and oscillations in the motor output , 1999, Experimental Brain Research.

[65]  T J Lewis,et al.  Self-organized synchronous oscillations in a network of excitable cells coupled by gap junctions , 2000, Network.

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

[67]  John Rinzel,et al.  Dynamics of Spiking Neurons Connected by Both Inhibitory and Electrical Coupling , 2003, Journal of Computational Neuroscience.

[68]  Nicolas Brunel,et al.  Fast Global Oscillations in Networks of Integrate-and-Fire Neurons with Low Firing Rates , 1999, Neural Computation.

[69]  S. Hughes,et al.  Just a phase they're going through: The complex interaction of intrinsic high-threshold bursting and gap junctions in the generation of thalamic α and θ rhythms , 2007 .

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

[71]  J. Martinerie,et al.  The brainweb: Phase synchronization and large-scale integration , 2001, Nature Reviews Neuroscience.

[72]  G. Dugué,et al.  Target-Dependent Use of Coreleased Inhibitory Transmitters at Central Synapses , 2005, The Journal of Neuroscience.

[73]  Heinke,et al.  Spike Transmission and Synchrony Detection in Networks of GABAergic Interneurons , 2022 .

[74]  S. Hestrin,et al.  Electrical synapses between Gaba-Releasing interneurons , 2001, Nature Reviews Neuroscience.

[75]  J M Bower,et al.  Oscillatory activity in the cerebellar hemispheres of unrestrained rats. , 1998, Journal of neurophysiology.

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

[77]  Wolf Singer,et al.  Neuronal Synchrony: A Versatile Code for the Definition of Relations? , 1999, Neuron.

[78]  E. Harley,et al.  Reversible inhibition of intercellular junctional communication by glycyrrhetinic acid. , 1986, Biochemical and biophysical research communications.

[79]  A. Pereda,et al.  Voltage-Dependent Enhancement of Electrical Coupling by a Subthreshold Sodium Current , 2004, The Journal of Neuroscience.

[80]  M. Bennett,et al.  Electrical Coupling and Neuronal Synchronization in the Mammalian Brain , 2004, Neuron.

[81]  D. Hansel,et al.  How Spike Generation Mechanisms Determine the Neuronal Response to Fluctuating Inputs , 2003, The Journal of Neuroscience.

[82]  J L van Hemmen,et al.  Time window control: a model for cerebellar function based on synchronization, reverberation, and time slicing. , 2000, Progress in brain research.

[83]  E De Schutter,et al.  Coding in the granular layer of the cerebellum. , 2001, Progress in brain research.

[84]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[85]  Michael A Long,et al.  Small Clusters of Electrically Coupled Neurons Generate Synchronous Rhythms in the Thalamic Reticular Nucleus , 2004, The Journal of Neuroscience.

[86]  J. Szentágothai,et al.  Quantitative histological analysis of the cerebellar cortex in the cat. I. Number and arrangement in space of the Purkinje cells. , 1971, Brain research.

[87]  N Kopell,et al.  Gap Junctions between Interneuron Dendrites Can Enhance Synchrony of Gamma Oscillations in Distributed Networks , 2001, The Journal of Neuroscience.

[88]  S. Hughes,et al.  Just a phase they're going through: the complex interaction of intrinsic high-threshold bursting and gap junctions in the generation of thalamic alpha and theta rhythms. , 2007, International journal of psychophysiology : official journal of the International Organization of Psychophysiology.

[89]  Michael A Long,et al.  Rhythmicity without Synchrony in the Electrically Uncoupled Inferior Olive , 2002, The Journal of Neuroscience.

[90]  B. Connors,et al.  A network of electrically coupled interneurons drives synchronized inhibition in neocortex , 2000, Nature Neuroscience.

[91]  Boris Barbour,et al.  Temporal Organization of Activity in the Cerebellar Cortex: A Manifesto for Synchrony , 2002, Annals of the New York Academy of Sciences.

[92]  S. Hestrin,et al.  A network of fast-spiking cells in the neocortex connected by electrical synapses , 1999, Nature.

[93]  J Szentágothai,et al.  Quantitative histological analysis of the cerebellar cortex in the cat. II. Cell numbers and densities in the granular layer. , 1971, Brain research.