Functional Coupling between mGluR1 and Cav3.1 T-Type Calcium Channels Contributes to Parallel Fiber-Induced Fast Calcium Signaling within Purkinje Cell Dendritic Spines

T-type voltage-gated calcium channels are expressed in the dendrites of many neurons, although their functional interactions with postsynaptic receptors and contributions to synaptic signaling are not well understood. We combine electrophysiological and ultrafast two-photon calcium imaging to demonstrate that mGluR1 activation potentiates cerebellar Purkinje cell Cav3.1 T-type currents via a G-protein- and tyrosine-phosphatase-dependent pathway. Immunohistochemical and electron microscopic investigations on wild-type and Cav3.1 gene knock-out animals show that Cav3.1 T-type channels are preferentially expressed in Purkinje cell dendritic spines and colocalize with mGluR1s. We further demonstrate that parallel fiber stimulation induces fast subthreshold calcium signaling in dendritic spines and that the synaptic Cav3.1-mediated calcium transients are potentiated by mGluR1 selectively during bursts of excitatory parallel fiber inputs. Our data identify a new fast calcium signaling pathway in Purkinje cell dendritic spines triggered by short burst of parallel fiber inputs and mediated by T-type calcium channels and mGluR1s.

[1]  Arthur Konnerth,et al.  A new class of synaptic response involving calcium release in dendritic spines , 1998, Nature.

[2]  T. Knöpfel,et al.  Responses to Metabotropic Glutamate Receptor Activation in Cerebellar Purkinje Cells: Induction of an Inward Current , 1992, The European journal of neuroscience.

[3]  T. Snutch,et al.  Nickel Block of a Family of Neuronal Calcium Channels: Subtype- and Subunit-Dependent Action at Multiple Sites , 1996, The Journal of Membrane Biology.

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

[5]  J. Garthwaite,et al.  Pharmacological Characterization of Synaptic Transmission through mGluRs in Rat Cerebellar Slices , 1997, Neuropharmacology.

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

[7]  Marco Canepari,et al.  Ca2+ Ion Permeability and Single-Channel Properties of the Metabotropic Slow EPSC of Rat Purkinje Neurons , 2004, The Journal of Neuroscience.

[8]  G. Gregory,et al.  Activation of the neuroprotective ERK signaling pathway by fructose-1,6-bisphosphate during hypoxia involves intracellular Ca2+ and phospholipase C , 2002, Brain Research.

[9]  Edmund M. Talley,et al.  Differential Distribution of Three Members of a Gene Family Encoding Low Voltage-Activated (T-Type) Calcium Channels , 1999, The Journal of Neuroscience.

[10]  Bertil Hille,et al.  Phospholipase C in Living Cells , 2005, The Journal of general physiology.

[11]  G. Collingridge,et al.  Motor deficit and impairment of synaptic plasticity in mice lacking mGluR1 , 1994, Nature.

[12]  Michael Häusser,et al.  Dendritic Calcium Spikes Are Tunable Triggers of Cannabinoid Release and Short-Term Synaptic Plasticity in Cerebellar Purkinje Neurons , 2006, The Journal of Neuroscience.

[13]  B H Gähwiler,et al.  Low-Threshold Ca2+ Currents in Dendritic Recordings from Purkinje Cells in Rat Cerebellar Slice Cultures , 1997, The Journal of Neuroscience.

[14]  Masanobu Kano,et al.  Synaptically Driven Endocannabinoid Release Requires Ca2+-Assisted Metabotropic Glutamate Receptor Subtype 1 to Phospholipase C β4 Signaling Cascade in the Cerebellum , 2005, The Journal of Neuroscience.

[15]  Chien-Chang Chen,et al.  Abnormal coronary function in mice deficient in alpha1H T-type Ca2+ channels. , 2003, Science.

[16]  P. Barrett,et al.  T-type calcium channel regulation by specific G-protein βγ subunits , 2003, Nature.

[17]  Roberto Araya,et al.  The spine neck filters membrane potentials , 2006, Proceedings of the National Academy of Sciences.

[18]  M. Häusser,et al.  Compartmental models of rat cerebellar Purkinje cells based on simultaneous somatic and dendritic patch‐clamp recordings , 2001, The Journal of physiology.

[19]  S. Barone,et al.  Ontogeny of voltage-sensitive calcium channel α1A and α1E subunit expression and synaptic function in rat central nervous system , 2003 .

[20]  Olivier Poirot,et al.  Silencing of the Cav3.2 T‐type calcium channel gene in sensory neurons demonstrates its major role in nociception , 2005, The EMBO journal.

[21]  J. Lacaille,et al.  mGluR1/5 subtype‐specific calcium signalling and induction of long‐term potentiation in rat hippocampal oriens/alveus interneurones , 2006, The Journal of physiology.

[22]  Daesoo Kim,et al.  Lack of the Burst Firing of Thalamocortical Relay Neurons and Resistance to Absence Seizures in Mice Lacking α1G T-Type Ca2+ Channels , 2001, Neuron.

[23]  Chien-Chang Chen,et al.  Abnormal Coronary Function in Mice Deficient in α1H T-type Ca2+ Channels , 2003, Science.

[24]  M. Womack,et al.  Dendritic Control of Spontaneous Bursting in Cerebellar Purkinje Cells , 2004, The Journal of Neuroscience.

[25]  E. Perez-Reyes.  Molecular physiology of low-voltage-activated t-type calcium channels. , 2003, Physiological reviews.

[26]  D W Tank,et al.  Direct Measurement of Coupling Between Dendritic Spines and Shafts , 1996, Science.

[27]  F. Pouille,et al.  Dendro‐somatic distribution of calcium‐mediated electrogenesis in Purkinje cells from rat cerebellar slice cultures , 2000, The Journal of physiology.

[28]  M. Tsujita,et al.  Mutation of α1G T-type Calcium Channels in Mice Does Not Change Anesthetic Requirements for Loss of the Righting Reflex and Minimum Alveolar Concentration but Delays the Onset of Anesthetic Induction , 2007, Anesthesiology.

[29]  Marc Freichel,et al.  TRPC3 Channels Are Required for Synaptic Transmission and Motor Coordination , 2008, Neuron.

[30]  M. Weiergräber,et al.  Disturbances in glucose-tolerance, insulin-release, and stress-induced hyperglycemia upon disruption of the Ca(v)2.3 (alpha 1E) subunit of voltage-gated Ca(2+) channels. , 2002, Molecular endocrinology.

[31]  P. Jonas,et al.  Differential Gating and Recruitment of P/Q-, N-, and R-Type Ca2+ Channels in Hippocampal Mossy Fiber Boutons , 2007, The Journal of Neuroscience.

[32]  T. Knöpfel,et al.  Metabotropic glutamate receptors in the cerebellum with a focus on their function in Purkinje cells , 2008, The Cerebellum.

[33]  R. Tadayonnejad,et al.  Regulation of T-type calcium channels by Rho-associated kinase , 2007, Nature Neuroscience.

[34]  P. Barrett,et al.  A Mechanism for the Direct Regulation of T-Type Calcium Channels by Ca2+/Calmodulin-Dependent Kinase II , 2003, The Journal of Neuroscience.

[35]  W Hamish Mehaffey,et al.  Specific T-type calcium channel isoforms are associated with distinct burst phenotypes in deep cerebellar nuclear neurons. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[36]  F. Crépel,et al.  Developmental changes in agonist-induced retrograde signaling at parallel fiber-Purkinje cell synapses: role of calcium-induced calcium release. , 2007, Journal of neurophysiology.

[37]  F. Tempia,et al.  A‐Type potassium currents active at subthreshold potentials in mouse cerebellar purkinje cells , 2002, The Journal of physiology.

[38]  K. Campbell,et al.  CaV3.2 is the major molecular substrate for redox regulation of T‐type Ca2+ channels in the rat and mouse thalamus , 2006, The Journal of physiology.

[39]  B. Sabatini,et al.  State-Dependent Calcium Signaling in Dendritic Spines of Striatal Medium Spiny Neurons , 2004, Neuron.

[40]  Susumu Tonegawa,et al.  Thalamic Cav3.1 T-type Ca2+ channel plays a crucial role in stabilizing sleep. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[41]  O. Ottersen,et al.  Organization of Glutamate Receptors at the Synapse , 1997, The European journal of neuroscience.

[42]  C. Hansel,et al.  Climbing fiber-triggered metabotropic slow potentials enhance dendritic calcium transients and simple spike firing in cerebellar Purkinje cells , 2007, Molecular and Cellular Neuroscience.

[43]  P. Somogyi,et al.  The metabotropic glutamate receptor (mGluRlα) is concentrated at perisynaptic membrane of neuronal subpopulations as detected by immunogold reaction , 1993, Neuron.

[44]  John Garthwaite,et al.  Frequency detection and temporally dispersed synaptic signal association through a metabotropic glutamate receptor pathway , 1997, Nature.

[45]  E. Perez-Reyes,et al.  Nickel block of three cloned T-type calcium channels: low concentrations selectively block alpha1H. , 1999, Biophysical journal.

[46]  S. Tonegawa,et al.  Deficient cerebellar long-term depression and impaired motor learning in mGluR1 mutant mice , 1994, Cell.

[47]  R. W. Turner,et al.  CaV3 T‐type calcium channel isoforms differentially distribute to somatic and dendritic compartments in rat central neurons , 2006, The European journal of neuroscience.

[48]  George J. Augustine,et al.  Local calcium signalling by inositol-1,4,5-trisphosphate in Purkinje cell dendrites , 1998, Nature.

[49]  P. Barrett,et al.  T-type calcium channel regulation by specific G-protein betagamma subunits. , 2003, Nature.

[50]  B. Barbour,et al.  Properties of Unitary Granule Cell→Purkinje Cell Synapses in Adult Rat Cerebellar Slices , 2002, The Journal of Neuroscience.

[51]  T. Snutch,et al.  Selective Inhibition of Cav3.3 T-type Calcium Channels by Gαq/11-coupled Muscarinic Acetylcholine Receptors* , 2007, Journal of Biological Chemistry.

[52]  Shigeo Watanabe,et al.  Differential roles of two types of voltage-gated Ca2+ channels in the dendrites of rat cerebellar Purkinje neurons , 1998, Brain Research.

[53]  Bernardo L Sabatini,et al.  Neuronal Activity Regulates Diffusion Across the Neck of Dendritic Spines , 2005, Science.

[54]  W. Denk,et al.  Two types of calcium response limited to single spines in cerebellar Purkinje cells. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[55]  S. Nakanishi,et al.  Distribution of the mRNA for a metabotropic glutamate receptor (mGluR1) in the central nervous system: An in situ hybridization study in adult and developing rat , 1992, The Journal of comparative neurology.

[56]  B. Bean,et al.  Ionic Mechanisms of Burst Firing in Dissociated Purkinje Neurons , 2003, The Journal of Neuroscience.

[57]  T. Hirano,et al.  Src-family protein tyrosine kinase negatively regulates cerebellar long-term depression , 2008, Neuroscience Research.

[58]  Y. Izumi,et al.  Arachidonic acid rescues hippocampal long-term potentiation blocked by group I metabotropic glutamate receptor antagonists , 2000, Neuroscience.

[59]  J. Huguenard,et al.  PKC and polyamine modulation of GluR2‐deficient AMPA receptors in immature neocortical pyramidal neurons of the rat , 2007, The Journal of physiology.

[60]  A. Wenzel,et al.  Synapse‐specific localization of NMDA and GABAA receptor subunits revealed by antigen‐retrieval immunohistochemistry , 1998, The Journal of comparative neurology.

[61]  P. Strata,et al.  Characterization of the mGluR(1)-mediated electrical and calcium signaling in Purkinje cells of mouse cerebellar slices. , 2001, Journal of neurophysiology.

[62]  B. MacVicar,et al.  Muscarinic Enhancement of R-Type Calcium Currents in Hippocampal CA1 Pyramidal Neurons , 2006, The Journal of Neuroscience.

[63]  Benjamin Mathieu,et al.  Optical monitoring of neuronal activity at high frame rate with a digital random-access multiphoton (RAMP) microscope , 2008, Journal of Neuroscience Methods.

[64]  S. Vincent,et al.  Structure and functional expression of a member of the low voltage-activated calcium channel family. , 1993, Science.

[65]  D. Ogden,et al.  Evidence for Protein Tyrosine Phosphatase, Tyrosine Kinase, and G-Protein Regulation of the Parallel Fiber Metabotropic Slow EPSC of Rat Cerebellar Purkinje Neurons , 2003, The Journal of Neuroscience.

[66]  S. Wang,et al.  Coincidence detection in single dendritic spines mediated by calcium release , 2000, Nature Neuroscience.

[67]  D Yanagihara,et al.  mGluR1 in cerebellar Purkinje cells essential for long-term depression, synapse elimination, and motor coordination. , 2000, Science.

[68]  T. Knöpfel.  Two new non‐competitive mGlu1 receptor antagonists are potent tools to unravel functions of this mGlu receptor subtype , 2007, British journal of pharmacology.

[69]  Joseph P. Yuan,et al.  Activation of the TRPC1 cation channel by metabotropic glutamate receptor mGluR1 , 2003, Nature.

[70]  Philippe Isope,et al.  Low threshold calcium currents in rat cerebellar Purkinje cell dendritic spines are mediated by T‐type calcium channels , 2005, The Journal of physiology.

[71]  Roger D. Traub,et al.  High-Frequency Network Oscillations in Cerebellar Cortex , 2008, Neuron.