Postsynaptic GABAB receptor signalling enhances LTD in mouse cerebellar Purkinje cells

Long‐term depression (LTD) of excitatory transmission at cerebellar parallel fibre–Purkinje cell synapses is a form of synaptic plasticity crucial for cerebellar motor learning. Around the postsynaptic membrane of these synapses, B‐type γ‐aminobutyric acid receptor (GABABR), a Gi/o protein‐coupled receptor for the inhibitory transmitter GABA is concentrated and closely associated with type‐1 metabotropic glutamate receptors (mGluR1) whose signalling is a key factor for inducing LTD. We found that in cultured Purkinje cells, GABABR activation enhanced LTD of a glutamate‐evoked current (LTDglu), increasing the magnitude of depression. It has been reported that parallel fibre–Purkinje cell synapses receive a micromolar level of GABA spilt over from the synaptic terminals of the neighbouring GABAergic interneurons. This level of GABA was able to enhance LTDglu. Our pharmacological analyses revealed that the βγ subunits but not the α subunit of Gi/o protein mediated GABABR‐mediated LTDglu enhancement. Gi/o protein activation was sufficient to enhance LTDglu. In this respect, LTDglu enhancement is clearly distinguished from the previously reported GABABR‐mediated augmentation of an mGluR1‐coupled slow excitatory postsynaptic potential. Baclofen application for only the induction period of LTDglu was sufficient to enhance LTDglu, suggesting that GABABR signalling may modulate mechanisms underlying LTDglu induction. Baclofen augmented mGluR1‐coupled Ca2+ release from the intracellular stores in a Gi/o protein‐dependent manner. Therefore, GABABR‐mediated LTDglu enhancement is likely to result from augmentation of mGluR1 signalling. Furthermore, pharmacological inhibition of GABABR reduced the magnitude of LTD at parallel fibre–Purkinje cell synapses in cerebellar slices. These findings demonstrate a novel mechanism that would facilitate cerebellar motor learning.

[1]  B. Fredholm,et al.  G protein‐independent neuromodulatory action of adenosine on metabotropic glutamate signalling in mouse cerebellar Purkinje cells , 2007, The Journal of physiology.

[2]  Yasushi Kishimoto,et al.  Junctophilin‐mediated channel crosstalk essential for cerebellar synaptic plasticity , 2007, The EMBO journal.

[3]  Masahiko Watanabe,et al.  Phospholipase Cβ3 is distributed in both somatodendritic and axonal compartments and localized around perisynapse and smooth endoplasmic reticulum in mouse Purkinje cell subsets , 2007, The European journal of neuroscience.

[4]  Rob Leurs,et al.  Pharmacogenomic and structural analysis of constitutive g protein-coupled receptor activity. , 2007, Annual review of pharmacology and toxicology.

[5]  Chris I. De Zeeuw,et al.  αCaMKII Is Essential for Cerebellar LTD and Motor Learning , 2006, Neuron.

[6]  Y. Shinoda,et al.  Long‐lasting synaptic loss after repeated induction of LTD: independence to the means of LTD induction , 2006, The European journal of neuroscience.

[7]  Masahiko Watanabe,et al.  Complementary stripes of phospholipase Cβ3 and Cβ4 expression by Purkinje cell subsets in the mouse cerebellum , 2006 .

[8]  M. Pertseva,et al.  Molecular mechanisms for the effect of mastoparan on G proteins in tissues of vertebrates and invertebrates , 2006, Bulletin of Experimental Biology and Medicine.

[9]  Masahiko Watanabe,et al.  Maintenance of presynaptic function by AMPA receptor-mediated excitatory postsynaptic activity in adult brain. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[10]  M. Kano,et al.  GABAergic activation of an inwardly rectifying K+ current in mouse cerebellar Purkinje cells , 2005, The Journal of physiology.

[11]  Masahiko Watanabe,et al.  Signaling complex formation of phospholipase Cβ4 with metabotropic glutamate receptor type 1α and 1,4,5‐trisphosphate receptor at the perisynapse and endoplasmic reticulum in the mouse brain , 2004, The European journal of neuroscience.

[12]  M. Kano,et al.  Ca2+ activity at GABAB receptors constitutively promotes metabotropic glutamate signaling in the absence of GABA. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[13]  S. Nakanishi,et al.  Altered agonist sensitivity and desensitization of neuronal mGluR1 responses in knock‐in mice by a single amino acid substitution at the PKC phosphorylation site , 2004, The European journal of neuroscience.

[14]  M. Olianas,et al.  Positive regulation of GABA(B) receptors dually coupled to cyclic AMP by the allosteric agent CGP7930. , 2003, European journal of pharmacology.

[15]  R. Huganir,et al.  Requirement of AMPA Receptor GluR2 Phosphorylation for Cerebellar Long-Term Depression , 2003, Science.

[16]  Don-On Daniel Mak,et al.  A New Mode of Ca2+ Signaling by G Protein-Coupled Receptors Gating of IP3 Receptor Ca2+ Release Channels by Gβγ , 2003, Current Biology.

[17]  Masao Ito.  The molecular organization of cerebellar long-term depression , 2002, Nature Reviews Neuroscience.

[18]  R. Shigemoto,et al.  Distinct localization of GABAB receptors relative to synaptic sites in the rat cerebellum and ventrobasal thalamus , 2002, The European journal of neuroscience.

[19]  Tohru Yoshioka,et al.  GABAB receptor activation enhances mGluR-mediated responses at cerebellar excitatory synapses , 2001, Nature Neuroscience.

[20]  Toshihide Tabata,et al.  A reliable method for culture of dissociated mouse cerebellar cells enriched for Purkinje neurons , 2000, Journal of Neuroscience Methods.

[21]  J. Bolam,et al.  Cellular and sub-cellular localisation of GABA(B1) and GABA(B2) receptor proteins in the rat cerebellum. , 2000, Brain research. Molecular brain research.

[22]  Masahiko Watanabe,et al.  Critical Period for Activity-Dependent Synapse Elimination in Developing Cerebellum , 2000, The Journal of Neuroscience.

[23]  S. Mikawa,et al.  Disruption of AMPA receptor GluR2 clusters following long‐term depression induction in cerebellar Purkinje neurons , 2000, The EMBO journal.

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

[25]  Masahiko Watanabe,et al.  Gq protein α subunits Gαq and Gα11 are localized at postsynaptic extra‐junctional membrane of cerebellar Purkinje cells and hippocampal pyramidal cells , 2000, The European journal of neuroscience.

[26]  D. Linden,et al.  Expression of Cerebellar Long-Term Depression Requires Postsynaptic Clathrin-Mediated Endocytosis , 2000, Neuron.

[27]  M. Kano,et al.  Phospholipase cbeta4 is specifically involved in climbing fiber synapse elimination in the developing cerebellum. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Kenneth A. Jones,et al.  GABAB receptors function as a heteromeric assembly of the subunits GABABR1 and GABABR2 , 1998, Nature.

[29]  R. Shigemoto,et al.  GABAB-receptor subtypes assemble into functional heteromeric complexes , 1998, Nature.

[30]  D. Linden,et al.  Inositol-1,4,5-trisphosphate receptor-mediated Ca mobilization is not required for cerebellar long-term depression in reduced preparations. , 1998, Journal of neurophysiology.

[31]  K. Mikoshiba,et al.  Type 1 Inositol 1,4,5-Trisphosphate Receptor Is Required for Induction of Long-Term Depression in Cerebellar Purkinje Neurons , 1998, The Journal of Neuroscience.

[32]  S. Hill,et al.  G protein-coupled-receptor cross-talk: the fine-tuning of multiple receptor-signalling pathways. , 1998, Trends in pharmacological sciences.

[33]  W. Regehr,et al.  Mechanism and Kinetics of Heterosynaptic Depression at a Cerebellar Synapse , 1997, The Journal of Neuroscience.

[34]  P. Somogyi,et al.  Differential plasma membrane distribution of metabotropic glutamate receptors mGluR1α, mGluR2 and mGluR5, relative to neurotransmitter release sites , 1997, Journal of Chemical Neuroanatomy.

[35]  B. Bean,et al.  GABAB Receptor-Activated Inwardly Rectifying Potassium Current in Dissociated Hippocampal CA3 Neurons , 1996, The Journal of Neuroscience.

[36]  WG Regehr,et al.  Contributions of calcium-dependent and calcium-independent mechanisms to presynaptic inhibition at a cerebellar synapse , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

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

[38]  S. Nakanishi,et al.  Antibodies inactivating mGluR1 metabotropic glutamate receptor block long-term depression in cultured Purkinje cells , 1994, Neuron.

[39]  A. Marty,et al.  Calcium-induced calcium release in cerebellar purkinje cells , 1994, Neuron.

[40]  B. Bean,et al.  GABAB Receptor Inhibition of P-type Ca2+ Channels in Central Neurons , 1993, Neuron.

[41]  S. Rhee,et al.  Activation of phospholipase C isozymes by G protein beta gamma subunits. , 1993, The Journal of biological chemistry.

[42]  M. Dickinson,et al.  A long-term depression of AMPA currents in cultured cerebellar purkinje neurons , 1991, Neuron.

[43]  M. Ito,et al.  Messengers mediating long-term desensitization in cerebellar Purkinje cells. , 1990, Neuroreport.

[44]  E. Ross,et al.  Mastoparan, a peptide toxin from wasp venom, mimics receptors by activating GTP-binding regulatory proteins (G proteins). , 1988, The Journal of biological chemistry.

[45]  M. Palfreyman,et al.  The relationship between GABA concentrations in brain and cerebrospinal fluid , 1979, Brain Research.

[46]  G. Köhr,et al.  Role of heteromer formation in GABAB receptor function. , 1999, Science.

[47]  W T Thach,et al.  The cerebellum and the adaptive coordination of movement. , 1992, Annual review of neuroscience.