Molecular Layer Interneurons: Key Elements of Cerebellar Network Computation and Behavior

Molecular layer interneurons (MLIs) play an important role in cerebellar information processing by controlling Purkinje cell (PC) activity via inhibitory synaptic transmission. A local MLI network, constructed from both chemical and electrical synapses, is organized into spatially structured clusters that amplify feedforward and lateral inhibition to shape the temporal and spatial patterns of PC activity. Several recent in vivo studies indicate that such MLI circuits contribute not only to sensorimotor information processing, but also contribute to precise motor coordination and cognitive processes. Here, we review current understanding of the organization of MLI circuits and their roles in the function of the mammalian cerebellum.

[1]  Ben Deverett,et al.  Cerebellar granule cells acquire a widespread predictive feedback signal during motor learning , 2017, Nature Neuroscience.

[2]  C. Armstrong,et al.  Inhibitory synaptic currents in rat cerebellar Purkinje cells: modulation by postsynaptic depolarization. , 1992, The Journal of physiology.

[3]  George J Augustine,et al.  Serial processing of kinematic signals by cerebellar circuitry during voluntary whisking , 2017, Nature Communications.

[4]  D. Prince,et al.  Functional Autaptic Neurotransmission in Fast-Spiking Interneurons: A Novel Form of Feedback Inhibition in the Neocortex , 2003, The Journal of Neuroscience.

[5]  J. Delgado-García,et al.  Compromised Survival of Cerebellar Molecular Layer Interneurons Lacking GDNF Receptors GFRα1 or RET Impairs Normal Cerebellar Motor Learning , 2017, Cell reports.

[6]  Clinton B. McCracken,et al.  Neuronal gap junctions: expression, function, and implications for behavior. , 2006, International review of neurobiology.

[7]  C. G. Phillips,et al.  Excitatory and inhibitory processes acting upon individual Purkinje cells of the cerebellum in cats , 1956, The Journal of physiology.

[8]  J. Medina,et al.  The multiple roles of Purkinje cells in sensori-motor calibration: to predict, teach and command , 2011, Current Opinion in Neurobiology.

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

[10]  T. Otis,et al.  Excitation of cerebellar interneurons by group I metabotropic glutamate receptors. , 2004, Journal of neurophysiology.

[11]  E. D’Angelo,et al.  Seeking a unified framework for cerebellar function and dysfunction: from circuit operations to cognition , 2013, Front. Neural Circuits.

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

[13]  D. Tank,et al.  Widespread State-Dependent Shifts in Cerebellar Activity in Locomoting Mice , 2012, PloS one.

[14]  P. Strick,et al.  Cerebellum and nonmotor function. , 2009, Annual review of neuroscience.

[15]  Kenneth D. Harris,et al.  Diversity of Interneurons in the Dorsal Striatum Revealed by Single-Cell RNA Sequencing and PatchSeq , 2018, Cell reports.

[16]  Masahiko Watanabe,et al.  Ptf1a, a bHLH Transcriptional Gene, Defines GABAergic Neuronal Fates in Cerebellum , 2005, Neuron.

[17]  Eric Shea-Brown,et al.  Impact of Network Structure and Cellular Response on Spike Time Correlations , 2011, PLoS Comput. Biol..

[18]  Henrik Jörntell,et al.  Reciprocal Bidirectional Plasticity of Parallel Fiber Receptive Fields in Cerebellar Purkinje Cells and Their Afferent Interneurons , 2002, Neuron.

[19]  M. Perc,et al.  Regulation of Irregular Neuronal Firing by Autaptic Transmission , 2016, Scientific Reports.

[20]  R. Ivry,et al.  The Cerebellum: Adaptive Prediction for Movement and Cognition , 2017, Trends in Cognitive Sciences.

[21]  A. Marty,et al.  Concerted Interneuron Activity in the Cerebellar Molecular Layer During Rhythmic Oromotor Behaviors , 2017, The Journal of Neuroscience.

[22]  N. Lemkey-Johnston,et al.  The distribution of recurrent purkinje collateral synapses in the mouse cerebellar cortex: An electron microscopic study , 1970, The Journal of comparative neurology.

[23]  Tadashi Yamazaki,et al.  Modeling memory consolidation during posttraining periods in cerebellovestibular learning , 2015, Proceedings of the National Academy of Sciences.

[24]  T. Ebner,et al.  Imaging parallel fiber and climbing fiber responses and their short-term interactions in the mouse cerebellar cortex in vivo , 2004, Neuroscience.

[25]  Luke T. Coddington,et al.  Spillover-Mediated Feedforward Inhibition Functionally Segregates Interneuron Activity , 2013, Neuron.

[26]  Safiya I. Lahlaf,et al.  Purkinje Cell Collaterals Enable Output Signals from the Cerebellar Cortex to Feed Back to Purkinje Cells and Interneurons , 2016, Neuron.

[27]  C. Pouzat,et al.  Somatic Recording of GABAergic Autoreceptor Current in Cerebellar Stellate and Basket Cells , 1999, The Journal of Neuroscience.

[28]  Benjamin F. Cravatt,et al.  Retrograde endocannabinoid signaling in the cerebellar cortex , 2008, The Cerebellum.

[29]  C. Ekerot,et al.  Parallel fiber receptive fields: a key to understanding cerebellar operation and learning , 2008, The Cerebellum.

[30]  I. Llano,et al.  Activation of Metabotropic Glutamate Receptors Induces Periodic Burst Firing and Concomitant Cytosolic Ca2+ Oscillations in Cerebellar Interneurons , 2009, The Journal of Neuroscience.

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

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

[33]  Johannes J. Letzkus,et al.  Cortical feed-forward networks for binding different streams of sensory information , 2006, Nature Neuroscience.

[34]  Ian Duguid,et al.  Dendritic excitation–inhibition balance shapes cerebellar output during motor behaviour , 2016, Nature Communications.

[35]  B. Robertson,et al.  Patch-Clamp Recordings from Cerebellar Basket Cell Bodies and Their Presynaptic Terminals Reveal an Asymmetric Distribution of Voltage-Gated Potassium Channels , 1998, The Journal of Neuroscience.

[36]  Kamran Khodakhah,et al.  Cerebellar modulation of the reward circuitry and social behavior , 2019, Science.

[37]  E. D’Angelo,et al.  Diverse Neuron Properties and Complex Network Dynamics in the Cerebellar Cortical Inhibitory Circuit , 2019, Front. Mol. Neurosci..

[38]  Richard A. Muscat,et al.  Single-cell profiling of the developing mouse brain and spinal cord with split-pool barcoding , 2018, Science.

[39]  Andreea C. Bostan,et al.  Consensus Paper: Towards a Systems-Level View of Cerebellar Function: the Interplay Between Cerebellum, Basal Ganglia, and Cortex , 2016, The Cerebellum.

[40]  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.

[41]  Judy E. Anderson,et al.  The Cerebellum in Emotional Processing: Evidence from Human and Non-Human Animals , 2014 .

[42]  I. Llano,et al.  Spatial heterogeneity of intracellular Ca2+ signals in axons of basket cells from rat cerebellar slices , 1997, The Journal of physiology.

[43]  Karl Schilling,et al.  Besides Purkinje cells and granule neurons: an appraisal of the cell biology of the interneurons of the cerebellar cortex , 2008, Histochemistry and Cell Biology.

[44]  Alain Marty,et al.  Heterogeneity of Functional Synaptic Parameters among Single Release Sites , 1997, Neuron.

[45]  Alain Marty,et al.  Estimating functional connectivity in an electrically coupled interneuron network , 2013, Proceedings of the National Academy of Sciences.

[46]  Bernardo L Sabatini,et al.  Synapse-specific plasticity and compartmentalized signaling in cerebellar stellate cells , 2006, Nature Neuroscience.

[47]  M. Farrant,et al.  Variations on an inhibitory theme: phasic and tonic activation of GABAA receptors , 2005, Nature Reviews Neuroscience.

[48]  B. Clark,et al.  Activity-Dependent Recruitment of Extrasynaptic NMDA Receptor Activation at an AMPA Receptor-Only Synapse , 2002, The Journal of Neuroscience.

[49]  Kamran Khodakhah,et al.  The Role of Interneurons in Shaping Purkinje Cell Responses in the Cerebellar Cortex , 2011, The Journal of Neuroscience.

[50]  Ben Deverett,et al.  Normal cognitive and social development require posterior cerebellar activity , 2018, eLife.

[51]  Aviv Regev,et al.  A transcriptomic atlas of the mouse cerebellum reveals regional specializations and novel cell types , 2020, bioRxiv.

[52]  Masao Ito Control of mental activities by internal models in the cerebellum , 2008, Nature Reviews Neuroscience.

[53]  Henrik Jörntell,et al.  Cerebellar molecular layer interneurons – computational properties and roles in learning , 2010, Trends in Neurosciences.

[54]  T. Kawasaki,et al.  Short-term modulation of cerebellar Purkinje cell activity after spontaneous climbing fiber input. , 1992, Journal of neurophysiology.

[55]  Henrik Jörntell,et al.  Parallel fiber and climbing fiber responses in rat cerebellar cortical neurons in vivo , 2013, Front. Syst. Neurosci..

[56]  Y. Yarom,et al.  Cerebellar on-beam and lateral inhibition: two functionally distinct circuits. , 2000, Journal of neurophysiology.

[57]  Gang Chen,et al.  Cerebellar Cortical Molecular Layer Inhibition Is Organized in Parasagittal Zones , 2006, The Journal of Neuroscience.

[58]  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.

[59]  C. Sotelo Molecular Layer Interneurons of the Cerebellum: Developmental and Morphological Aspects , 2015, The Cerebellum.

[60]  Henrik Jörntell,et al.  Receptive Field Plasticity Profoundly Alters the Cutaneous Parallel Fiber Synaptic Input to Cerebellar Interneurons In Vivo , 2003, The Journal of Neuroscience.

[61]  Angelo Arleo,et al.  Contribution of Cerebellar Sensorimotor Adaptation to Hippocampal Spatial Memory , 2012, PloS one.

[62]  George J Augustine,et al.  Optogenetic mapping of cerebellar inhibitory circuitry reveals spatially biased coordination of interneurons via electrical synapses. , 2014, Cell reports.

[63]  W. C. Hall,et al.  High-speed mapping of synaptic connectivity using photostimulation in Channelrhodopsin-2 transgenic mice , 2007, Proceedings of the National Academy of Sciences.

[64]  M. Häusser,et al.  Microcircuit Rules Governing Impact of Single Interneurons on Purkinje Cell Output In Vivo , 2020, Cell reports.

[65]  J. Bower,et al.  Feedforward inhibition controls the spread of granule cell-induced Purkinje cell activity in the cerebellar cortex. , 2007, Journal of neurophysiology.

[66]  C. Pouzat,et al.  Developmental Regulation of Basket/Stellate Cell→Purkinje Cell Synapses in the Cerebellum , 1997, The Journal of Neuroscience.

[67]  Masao Ito,et al.  The Cerebellum: Brain for an Implicit Self , 2011 .

[68]  Boris Barbour,et al.  Multiple climbing fibers signal to molecular layer interneurons exclusively via glutamate spillover , 2007, Nature Neuroscience.

[69]  Nan Miao,et al.  Revealing cellular and molecular complexity of the central nervous system using single cell sequencing , 2018, Stem Cell Research & Therapy.

[70]  S. Palay,et al.  Cerebellar Cortex: Cytology and Organization , 1974 .

[71]  M. Garwicz,et al.  Anatomical and physiological foundations of cerebellar information processing , 2005, Nature Reviews Neuroscience.

[72]  Stuart G. Cull-Candy,et al.  Synaptic activity at calcium-permeable AMPA receptors induces a switch in receptor subtype , 2000, Nature.

[73]  Christophe Pouzat,et al.  Autaptic inhibitory currents recorded from interneurones in rat cerebellar slices , 1998, The Journal of physiology.

[74]  Evan Z. Macosko,et al.  Slide-seq: A scalable technology for measuring genome-wide expression at high spatial resolution , 2019, Science.

[75]  George J Augustine,et al.  Precise Control of Movement Kinematics by Optogenetic Inhibition of Purkinje Cell Activity , 2014, The Journal of Neuroscience.

[76]  Masahiko Watanabe,et al.  Lack of Molecular–Anatomical Evidence for GABAergic Influence on Axon Initial Segment of Cerebellar Purkinje Cells by the Pinceau Formation , 2012, The Journal of Neuroscience.

[77]  M. Häusser,et al.  Tonic Synaptic Inhibition Modulates Neuronal Output Pattern and Spatiotemporal Synaptic Integration , 1997, Neuron.

[78]  H. Mitoma,et al.  Monoaminergic long-term facilitation of GABA-mediated inhibitory transmission at cerebellar synapses , 1999, Neuroscience.

[79]  Jason R Pugh,et al.  Biphasic modulation of parallel fibre synaptic transmission by co‐activation of presynaptic GABAA and GABAB receptors in mice , 2016, The Journal of physiology.

[80]  K. Khodakhah,et al.  Efficient generation of reciprocal signals by inhibition. , 2012, Journal of neurophysiology.

[81]  Jacqueline N. Crawley,et al.  Autistic-like behavior and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice , 2012, Nature.

[82]  Arnd Roth,et al.  Structured Connectivity in Cerebellar Inhibitory Networks , 2014, Neuron.

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

[84]  H. Axelrad,et al.  Lugaro cells target basket and stellate cells in the cerebellar cortex , 1998, Neuroreport.

[85]  Evan Z. Macosko,et al.  Molecular Diversity and Specializations among the Cells of the Adult Mouse Brain , 2018, Cell.

[86]  Mihaly Kollo,et al.  Novel Subcellular Distribution Pattern of A-Type K+ Channels on Neuronal Surface , 2006, The Journal of Neuroscience.

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

[88]  Daniela Popa,et al.  Cerebellum involvement in cortical sensorimotor circuits for the control of voluntary movements , 2014, Nature Neuroscience.

[89]  Catherine Limperopoulos,et al.  Does Cerebellar Injury in Premature Infants Contribute to the High Prevalence of Long-term Cognitive, Learning, and Behavioral Disability in Survivors? , 2007, Pediatrics.

[90]  Jennifer L. Hadley,et al.  A Single-Cell Transcriptional Atlas of the Developing Murine Cerebellum , 2018, Current Biology.

[91]  G. I. Hatton,et al.  SYNAPTIC MODULATION OF NEURONAL COUPLING , 1998, Cell biology international.

[92]  F. Rossi,et al.  Handbook of the Cerebellum and Cerebellar Disorders , 2013, Springer Netherlands.

[93]  Aleksandra Badura,et al.  The Cerebellum, Sensitive Periods, and Autism , 2014, Neuron.

[94]  Eduardo Ros,et al.  Modeling the Cerebellar Microcircuit: New Strategies for a Long-Standing Issue , 2016, Front. Cell. Neurosci..

[95]  Karl Deisseroth,et al.  Next-generation transgenic mice for optogenetic analysis of neural circuits , 2013, Front. Neural Circuits.

[96]  T. Sakaba,et al.  Target-Dependent Feedforward Inhibition Mediated by Short-Term Synaptic Plasticity in the Cerebellum , 2010, The Journal of Neuroscience.

[97]  J. Szentágothai,et al.  Identification of synapses formed in the cerebellar cortex by purkinje axon collaterals: an electron microscope study , 2004, Experimental Brain Research.

[98]  G. Feng,et al.  Cell type–specific channelrhodopsin-2 transgenic mice for optogenetic dissection of neural circuitry function , 2011, Nature Methods.

[99]  Martijn Schonewille,et al.  Dysfunctional cerebellar Purkinje cells contribute to autism-like behaviour in Shank2-deficient mice , 2016, Nature Communications.

[100]  Richard Hawkes,et al.  The compartmental restriction of cerebellar interneurons , 2013, Front. Neural Circuits.

[101]  William Wisden,et al.  Synaptic inhibition of Purkinje cells mediates consolidation of vestibulo-cerebellar motor learning , 2009, Nature Neuroscience.

[102]  Arne Møller,et al.  Total numbers of various cell types in rat cerebellar cortex estimated using an unbiased stereological method , 1993, Brain Research.

[103]  Roy V. Sillitoe,et al.  New roles for the cerebellum in health and disease , 2013, Front. Syst. Neurosci..

[104]  Specification and Development of GABAergic Interneurons , 2019, Handbook of the Cerebellum and Cerebellar Disorders.

[105]  M. Zhang,et al.  Single-cell transcriptomes reveal molecular specializations of neuronal cell types in the developing cerebellum , 2019, Journal of molecular cell biology.

[106]  James M. Bower,et al.  Model-Founded Explorations of the Roles of Molecular Layer Inhibition in Regulating Purkinje Cell Responses in Cerebellar Cortex: More Trouble for the Beam Hypothesis , 2010, Front. Cell. Neurosci..

[107]  Peer Wulff,et al.  Evolving Models of Pavlovian Conditioning: Cerebellar Cortical Dynamics in Awake Behaving Mice , 2015, Cell reports.

[108]  Iaroslav Savtchouk,et al.  A single fear-inducing stimulus induces a transcription-dependent switch in AMPA receptor phenotype , 2009, Nature Neuroscience.

[109]  K. Mackie,et al.  Short-Term Retrograde Inhibition of GABAergic Synaptic Currents in Rat Purkinje Cells Is Mediated by Endogenous Cannabinoids , 2002, The Journal of Neuroscience.

[110]  George J. Augustine,et al.  Graded Control of Climbing-Fiber-Mediated Plasticity and Learning by Inhibition in the Cerebellum , 2018, Neuron.

[111]  S. Dieudonné Book Review: Serotonergic Neuromodulation in the Cerebellar Cortex: Cellular, Synaptic, and Molecular Basis , 2001, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[112]  M. Ito,et al.  Cerebellar long-term depression: characterization, signal transduction, and functional roles. , 2001, Physiological reviews.

[113]  A. Marty,et al.  Differential effects of noradrenaline on evoked, spontaneous and miniature IPSCs in rat cerebellar stellate cells , 1998, The Journal of physiology.

[114]  Michael A. Gaffield,et al.  Movement Rate Is Encoded and Influenced by Widespread, Coherent Activity of Cerebellar Molecular Layer Interneurons , 2017, The Journal of Neuroscience.

[115]  Andreas Zimmer,et al.  The Cannabinoid CB1 Receptor Mediates Retrograde Signals for Depolarization-Induced Suppression of Inhibition in Cerebellar Purkinje Cells , 2002, The Journal of Neuroscience.

[116]  G. Bishop An analysis of HRP-filled basket cell axons in the cat's cerebellum , 1993, Anatomy and Embryology.

[117]  K. Svoboda,et al.  Channelrhodopsin-2–assisted circuit mapping of long-range callosal projections , 2007, Nature Neuroscience.

[118]  V. Chan‐Palay,et al.  The recurrent collaterals of Purkinje cell axons: A correlated study of the rat's cerebellar cortex with electron microscopy and the Golgi method , 2004, Zeitschrift für Anatomie und Entwicklungsgeschichte.

[119]  A. Marty,et al.  Fluctuations of inhibitory postsynaptic currents in Purkinje cells from rat cerebellar slices. , 1996, The Journal of physiology.

[120]  G. Bishop,et al.  Physiological and anatomical studies of the interactions between Purkinje cells and basket cells in the cat's cerebellar cortex: evidence for a unitary relationship , 1989, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[121]  Vanessa A. Bender,et al.  Presynaptically Expressed Long-Term Potentiation Increases Multivesicular Release at Parallel Fiber Synapses , 2009, The Journal of Neuroscience.

[122]  A. Marty,et al.  Enhancement of GABA Release through Endogenous Activation of Axonal GABAA Receptors in Juvenile Cerebellum , 2007, The Journal of Neuroscience.

[123]  Masao Ito The Cerebellum And Neural Control , 1984 .

[124]  G. Bishop,et al.  An analysis of HRP-filled basket cell axons in the cat's cerebellum , 1993, Anatomy and Embryology.

[125]  A. Marty,et al.  Synaptic currents at individual connections among stellate cells in rat cerebellar slices , 1998, The Journal of physiology.

[126]  Tobias Rose,et al.  Optimizing the spatial resolution of Channelrhodopsin-2 activation , 2008, Brain cell biology.

[127]  Marc P. Waase,et al.  Selective Loss of Presynaptic Potassium Channel Clusters at the Cerebellar Basket Cell Terminal Pinceau in Adam11 Mutants Reveals Their Role in Ephaptic Control of Purkinje Cell Firing , 2015, The Journal of Neuroscience.

[128]  H. Sompolinsky,et al.  Chaos in Neuronal Networks with Balanced Excitatory and Inhibitory Activity , 1996, Science.

[129]  J M Bower,et al.  Quantitative Golgi study of the rat cerebellar molecular layer interneurons using principal component analysis , 1998, The Journal of comparative neurology.

[130]  Boris Barbour,et al.  Ultra-rapid axon-axon ephaptic inhibition of cerebellar Purkinje cells by the pinceau , 2014, Nature Neuroscience.

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

[132]  H. Gerschenfeld,et al.  Inhibitory synaptic currents in stellate cells of rat cerebellar slices. , 1993, The Journal of physiology.

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

[134]  Travis A. Jarrell,et al.  The Connectome of a Decision-Making Neural Network , 2012, Science.

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

[136]  Wade G. Regehr,et al.  Local Interneurons Regulate Synaptic Strength by Retrograde Release of Endocannabinoids , 2006, The Journal of Neuroscience.

[137]  P. Isope,et al.  Short-term plasticity at cerebellar granule cell to molecular layer interneuron synapses expands information processing , 2019, eLife.

[138]  Jean-Luc Dupont,et al.  Stereotyped spatial patterns of functional synaptic connectivity in the cerebellar cortex , 2015, eLife.

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