Synaptic and Cellular Properties of the Feedforward Inhibitory Circuit within the Input Layer of the Cerebellar Cortex

Precise representation of the timing of sensory stimuli is essential for rapid motor coordination, a core function of the cerebellum. Feedforward inhibition has been implicated in precise temporal signaling in several regions of the brain, but little is known about this type of inhibitory circuit within the input layer of the cerebellar cortex. We investigated the synaptic properties of feedforward inhibition at near physiological temperatures (35°C) in rat cerebellar slices. We establish that the previously uncharacterized mossy fiber–Golgi cell–granule cell pathway can act as a functional feedforward inhibitory circuit. The synchronous activation of four mossy fibers, releasing a total of six quanta onto a Golgi cell, can reset spontaneous Golgi cell firing with high temporal precision (200 μs). However, only modest increases in Golgi cell firing rate were observed during trains of high-frequency mossy fiber stimulation. This decoupling of Golgi cell activity from mossy fiber firing rate was attributable to a strong afterhyperpolarization after each action potential, preventing mossy fiber–Golgi cell signaling for ∼50 ms. Feedforward excitation of Golgi cells induced a temporally precise inhibitory conductance in granule cells that curtailed the excitatory action of the mossy fiber EPSC. The synaptic and cellular properties of this feedforward circuit appear tuned to trigger a fast inhibitory conductance in granule cells at the onset of stimuli that produce intense bursts of activity in multiple mossy fibers, thereby conserving the temporal precision of the initial granule cell response.

[1]  Arnd Roth,et al.  Submillisecond AMPA Receptor-Mediated Signaling at a Principal Neuron–Interneuron Synapse , 1997, Neuron.

[2]  Michael Häusser,et al.  Feed‐forward inhibition shapes the spike output of cerebellar Purkinje cells , 2005, The Journal of physiology.

[3]  Prof. Dr. Sanford L. Palay,et al.  Cerebellar Cortex , 1974, Springer Berlin Heidelberg.

[4]  Mark J. Wall,et al.  Development of Action Potential‐dependent and Independent Spontaneous GABAA Receptor‐mediated Currents in Granule Cells of Postnatal Rat Cerebellum , 1997, The European journal of neuroscience.

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

[6]  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.

[7]  E E Fetz,et al.  Relation between shapes of post‐synaptic potentials and changes in firing probability of cat motoneurones , 1983, The Journal of physiology.

[8]  G. Buzsáki,et al.  Spike train dynamics predicts theta-related phase precession in hippocampal pyramidal cells , 2002, Nature.

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

[10]  N. Barmack,et al.  Functions of Interneurons in Mouse Cerebellum , 2008, The Journal of Neuroscience.

[11]  B. Walmsley,et al.  Counting quanta: Direct measurements of transmitter release at a central synapse , 1995, Neuron.

[12]  Thomas A Nielsen,et al.  Desensitization Properties of AMPA Receptors at the Cerebellar Mossy Fiber–Granule Cell Synapse , 2007, The Journal of Neuroscience.

[13]  Ivan Cohen,et al.  The Beat Goes On: Spontaneous Firing in Mammalian Neuronal Microcircuits , 2004, The Journal of Neuroscience.

[14]  Troy W. Margrie,et al.  Neuronal Oscillations Enhance Stimulus Discrimination by Ensuring Action Potential Precision , 2006, PLoS Biology.

[15]  Wade G. Regehr,et al.  Quantal events shape cerebellar interneuron firing , 2002, Nature Neuroscience.

[16]  G. Ermentrout,et al.  Analysis of neural excitability and oscillations , 1989 .

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

[18]  M Lidierth,et al.  The discharges of cerebellar Golgi cells during locomotion in the cat. , 1987, The Journal of physiology.

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

[20]  G. Laurent,et al.  Impaired odour discrimination on desynchronization of odour-encoding neural assemblies , 1997, Nature.

[21]  Kamran Khodakhah,et al.  Decreases in the precision of Purkinje cell pacemaking cause cerebellar dysfunction and ataxia , 2006, Nature Neuroscience.

[22]  R. Silver,et al.  Fast vesicle reloading and a large pool sustain high bandwidth transmission at a central synapse , 2006, Nature.

[23]  E. Neher,et al.  Release kinetics, quantal parameters and their modulation during short‐term depression at a developing synapse in the rat CNS , 2005, The Journal of physiology.

[24]  Matteo Carandini,et al.  Somatosensory Integration Controlled by Dynamic Thalamocortical Feed-Forward Inhibition , 2005, Neuron.

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

[26]  R. Llinás.  The intrinsic electrophysiological properties of mammalian neurons: insights into central nervous system function. , 1988, Science.

[27]  B. Barrell,et al.  Glutamate spillover suppresses inhibition by activating presynaptic mGluRs , 2000, Nature.

[28]  C. Stevens,et al.  The kinetics of transmitter release at the frog neuromuscular junction , 1972, The Journal of physiology.

[29]  P. Jonas,et al.  Distal initiation and active propagation of action potentials in interneuron dendrites. , 2000, Science.

[30]  W. Regehr,et al.  Differential Expression of Posttetanic Potentiation and Retrograde Signaling Mediate Target-Dependent Short-Term Synaptic Plasticity , 2007, Neuron.

[31]  R. Silver,et al.  Spillover of Glutamate onto Synaptic AMPA Receptors Enhances Fast Transmission at a Cerebellar Synapse , 2002, Neuron.

[32]  D. Angelaki,et al.  Purkinje Cells in Posterior Cerebellar Vermis Encode Motion in an Inertial Reference Frame , 2007, Neuron.

[33]  E De Schutter,et al.  Cerebellar Golgi cells in the rat: receptive fields and timing of responses to facial stimulation , 1999, The European journal of neuroscience.

[34]  S. Keele,et al.  Timing Functions of The Cerebellum , 1989, Journal of Cognitive Neuroscience.

[35]  David A DiGregorio,et al.  Changes in synaptic structure underlie the developmental speeding of AMPA receptor–mediated EPSCs , 2005, Nature Neuroscience.

[36]  Thomas A. Nielsen,et al.  Rapid Vesicular Release, Quantal Variability, and Spillover Contribute to the Precision and Reliability of Transmission at a Glomerular Synapse , 2005, The Journal of Neuroscience.

[37]  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.

[38]  J. Houk,et al.  Movement-related inputs to intermediate cerebellum of the monkey. , 1993, Journal of neurophysiology.

[39]  I. Rosén,et al.  Cerebellar surface cooling influencing evoked activity in cortex and in interpositus nucleus. , 1972, Brain research.

[40]  R. Miles,et al.  Synaptic excitation of inhibitory cells by single CA3 hippocampal pyramidal cells of the guinea‐pig in vitro. , 1990, The Journal of physiology.

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

[42]  R. Angus Silver,et al.  Estimation of nonuniform quantal parameters with multiple-probability fluctuation analysis: theory, application and limitations , 2003, Journal of Neuroscience Methods.

[43]  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.

[44]  M. Scanziani,et al.  Enforcement of Temporal Fidelity in Pyramidal Cells by Somatic Feed-Forward Inhibition , 2001, Science.

[45]  R. Silver,et al.  Non‐NMDA glutamate receptor occupancy and open probability at a rat cerebellar synapse with single and multiple release sites. , 1996, The Journal of physiology.

[46]  R. Morris.  Foundations of cellular neurophysiology , 1996 .

[47]  G. Orlovsky.  Activity of rubrospinal neurons during locomotion. , 1972, Brain research.

[48]  N. Tamamaki,et al.  Hippocampal pyramidal cells excite inhibitory neurons through a single release site , 1993, Nature.

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

[50]  Michael J. Berry,et al.  Refractoriness and Neural Precision , 1997, The Journal of Neuroscience.

[51]  Javier F. Medina,et al.  Computer simulation of cerebellar information processing , 2000, Nature Neuroscience.

[52]  L. Cathala,et al.  Developmental Profile of the Changing Properties of NMDA Receptors at Cerebellar Mossy Fiber–Granule Cell Synapses , 2000, The Journal of Neuroscience.

[53]  A. Konnerth,et al.  Synaptic‐ and agonist‐induced excitatory currents of Purkinje cells in rat cerebellar slices. , 1991, The Journal of physiology.

[54]  William Bialek,et al.  Spikes: Exploring the Neural Code , 1996 .

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

[56]  Richard Miles,et al.  EPSP Amplification and the Precision of Spike Timing in Hippocampal Neurons , 2000, Neuron.

[57]  Mark Farrant,et al.  Maturation of EPSCs and Intrinsic Membrane Properties Enhances Precision at a Cerebellar Synapse , 2003, The Journal of Neuroscience.

[58]  R. Silver,et al.  Locus of frequency‐dependent depression identified with multiple‐probability fluctuation analysis at rat climbing fibre‐Purkinje cell synapses , 1998, The Journal of physiology.

[59]  M. Häusser,et al.  High-fidelity transmission of sensory information by single cerebellar mossy fibre boutons , 2007, Nature.

[60]  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.