Persistent Multiple Climbing Fiber Innervationof Cerebellar Purkinje Cellsin Mice Lacking mGluR1

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Neural circuits are initially redundant but rearranged through activity-dependent synapse elimination during postnatal development. This process is crucial for shaping mature neural circuits and for proper brain function. At birth, Purkinje cells (PCs) in the cerebellum are innervated by multiple climbing fibers (CFs) with similar synaptic strengths. During postnatal development, a single CF is selectively strengthened in each PC through synaptic competition, the strengthened single CF undergoes translocation to a PC dendrite, and massive elimination of redundant CF synapses follows. To investigate the cellular mechanisms of this activity-dependent synaptic refinement, we generated mice with PC-selective deletion of the Ca v 2.1 P/Q-type Ca 2+ channel, the major voltage-dependent Ca 2+ channel in PCs. In the PC-selective Ca v 2.1 knockout mice, Ca 2+ transients induced by spontaneous CF inputs are markedly reduced in PCs in vivo. Not a single but multiple CFs were equally strengthened in each PC from postnatal day 5 (P5) to P8, multiple CFs underwent translocation to PC dendrites, and subsequent synapse elimination until around P12 was severely impaired. Thus, P/Q-type Ca 2+ channels in postsynaptic PCs mediate synaptic competition among multiple CFs and trigger synapse elimination in developing cerebellum.

Section: Resultsmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Postsynaptic P/Q-type Ca ²⁺ channel in Purkinje cell mediates synaptic competition and elimination in developing cerebellum

Hashimoto

Teräs

Miyazaki

et al. 2011

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101

113

“…mGluR1/5s play an important role in the establishment of synaptic circuitry during brain development (3,4) and in activity-dependent forms of synaptic plasticity, including long-term potentiation and long-term depression as occur in associative learning (5)(6)(7)(8). Dysregulated mGluR1/5 signaling is implicated in neurological, psychiatric, and cognitive disorders (8), including fragile X syndrome, the most common inherited cause of intellectual disabilities (9,10).…”

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confidence: 99%

Caveolin-1 knockout mice exhibit impaired induction of mGluR-dependent long-term depression at CA3-CA1 synapses

Takayasu

Takeuchi

Kumari

et al. 2010

Group I metabotropic glutamate receptors (mGluR1/5) are important to synaptic circuitry formation during development and to forms of activity-dependent synaptic plasticity. Dysregulation of mGluR1/5 signaling is implicated in some disorders of neurodevelopment, including fragile X syndrome, the most common inherited form of intellectual disabilities and leading cause of autism. Site(s) in the intracellular loops of mGluR1/5 directly bind caveolin-1, an adaptor protein that associates with membrane rafts. Caveolin-1 is the main coat component of caveolae and organizes macromolecular signaling complexes with effector proteins and membrane receptors. We report that long-term depression (LTD) elicited by a single application of the group I mGluR selective agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) was markedly attenuated at Schaffer collateral-CA1 synapses of mice lacking caveolin-1 (Cav1 −/− ), as assessed by field recording. In contrast, multiple applications of DHPG produced LTD comparable to that in WT mice. Passive membrane properties, basal glutamatergic transmission and NMDA receptor (NMDAR)-dependent LTD were unaltered. The remaining LTD was reduced by anisomycin, an inhibitor of protein synthesis, by U0126, an inhibitor of MEK1/2 kinases, and by rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), suggesting mediation by the same mechanisms as in WT. mGluR1/5-dependent activation (phosphorylation) of MEK and extracellular signal-regulated kinase (ERK1/2) was altered in Cav1 −/− mice; basal phosphorylation was increased, but a single application of DHPG had no further effect, and after DHPG, phosphorylation was similar in WT and Cav1 −/− mice. Taken together, our findings suggest that caveolin-1 is required for normal coupling of mGluR1/5 to downstream signaling cascades and induction of mGluR-LTD.G roup I metabotropic glutamate receptors (mGluRs), mGluR1 and mGluR5, are G protein-coupled receptors enriched at excitatory synapses throughout the brain, where they regulate neuronal excitation (1, 2). mGluR1/5s play an important role in the establishment of synaptic circuitry during brain development (3, 4) and in activity-dependent forms of synaptic plasticity, including long-term potentiation and long-term depression as occur in associative learning (5-8). Dysregulated mGluR1/5 signaling is implicated in neurological, psychiatric, and cognitive disorders (8), including fragile X syndrome, the most common inherited cause of intellectual disabilities (9, 10). The broad spectrum of physiological and pathological functions in which mGluRs participate is related to their capacity to initiate diverse signaling events by G protein-dependent and -independent mechanisms (11,12).Membrane rafts (13, 14) and caveolae (15) are specialized membrane domains of the plasma membrane, enriched in cholesterol and glycosphingolipids, that serve as platforms to compartmentalize specific signaling activities at the cell surface. Caveolin-1 is an adaptor protein that interacts with an array of receptors, including m...

“…Given that Ca o 2ϩ -GABA B R interaction does not trigger diffusible G protein signaling (12), Ca o 2ϩ activity at GABA B R is likely to influence a local target(s). A possible target is metabotropic glutamate receptor 1 (mGluR1) (15,16), which is expressed in many central neurons and mediates slow postsynaptic potentials (17,18), intracellular Ca 2ϩ mobilization (19)(20)(21), synaptic plasticity (22)(23)(24)(25), and developmental synapse elimination (24,26). In cerebellar Purkinje cells, mGluR1 colocalizes with GABA B R at the annuli of the dendritic spines innervated by excitatory parallel fibers (7,27).…”

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Ca ²⁺ activity at GABA _B receptors constitutively promotes metabotropic glutamate signaling in the absence of GABA

Tabata

Araishi

Hashimoto

et al. 2004

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Type B ␥-aminobutyric acid receptor (GABABR) is a G proteincoupled receptor that regulates neurotransmitter release and neuronal excitability throughout the brain. In various neurons, GABA BRs are concentrated at excitatory synapses. Although these receptors are assumed to respond to GABA spillover from neighboring inhibitory synapses, their function is not fully understood. Here we show a previously undescribed function of GABA BR exerted independent of GABA. In cerebellar Purkinje cells, interaction of GABA BR with extracellular Ca 2؉ (Ca o 2؉ ) leads to a constitutive increase in the glutamate sensitivity of metabotropic glutamate receptor 1 (mGluR1). mGluR1 sensitization is clearly mediated by GABA BR because it is absent in GABABR1 subunitknockout cells. However, the mGluR1 sensitization does not require G i/o proteins that mediate the GABABR's classical functions. Moreover, coimmunoprecipitation reveals complex formation between GABA BR and mGluR1 in the cerebellum. These findings demonstrate that GABA BR can act as Ca o 2؉ -dependent cofactors to enhance neuronal metabotropic glutamate signaling.T he type B ␥-aminobutyric acid receptor (GABA B R) is a G protein-coupled receptor (GPCR) distributed throughout the brain (1-3). GABA B R regulates neurotransmitter release and neuronal excitability via G i/o proteins (4). In the classic view, GABA B R responds to GABA released from inhibitory presynaptic terminals (4). However, in some central neurons including cerebellar Purkinje cells, postsynaptic GABA B Rs are concentrated perisynaptically at the excitatory synapses and present sparsely at the inhibitory synapses (5-7). Because GABA B Rs are insensitive to the excitatory neurotransmitter glutamate, a physiological role of GABA B R at excitatory synapses was assumed to depend on ␥-aminobutyric acid (GABA) spillover from neighboring inhibitory synapses (8, 9).The extracellular domain of GABA B R has an amino acid sequence homology to that of Ca 2ϩ -sensing receptor (CaR) (10). Some studies in the heterologous expression systems (11,12) revealed that GABA B R indeed interacts with extracellular Ca 2ϩ (Ca o 2ϩ ). Point mutation experiments indicate that the proximity of the GABA-binding site of GABA B R1 subunit (GBR1) is responsible for this interaction (11). Although Ca o 2ϩ -GABA B R interaction does not activate G proteins (12), it causes a remarkable conformational change of GABA B R as Ca o 2ϩ allosterically shifts GABA-GABA B R affinity (11,12 (22-25), and developmental synapse elimination (24, 26). In cerebellar Purkinje cells, mGluR1 colocalizes with GABA B R at the annuli of the dendritic spines innervated by excitatory parallel fibers (7,27). We have previously shown that mGluR1 signaling in Purkinje cells is enhanced as a consequence of interaction between Ca o 2ϩ and an unknown surface molecule(s) (28). For the reasons mentioned above, we considered GABA B R as a likely candidate for such a surface molecule.In Purkinje cells, mGluR1 outnumbers the other mGluR subtypes (16) and operates an inward ca...