Differential Regulation of Synaptic Plasticity and Cerebellar Motor Learning by the C-Terminal PDZ-Binding Motif of GluRδ2

Kakegawa, Wataru; Miyazaki, Toru; Emi, Kyoichi; Matsuda, Keiko; Kohda, Kazuhisa; Motohashi, Junko; Mishina, Masayoshi; Kawahara, Shigenori; Watanabe, Masahiko; Yuzaki, Michisuke

doi:10.1523/jneurosci.2553-07.2008

Cited by 84 publications

(77 citation statements)

References 40 publications

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“…Purkinje-cell-specific Atg5-deficient mice (Atg5 flox/flox ; pcp2-Cre) were generated as described previously (Nishiyama et al, 2007) and crossed with Lc/ϩ mice (B6CBACa A w-J /A-Grid2 Lc /J; The Jackson Laboratory). GluD2 wt and GluD2 wt -⌬CT7 transgenic mice on a GluD2-null background were generated as described previously (Kakegawa et al, 2008). Genotypes were determined by PCR analysis of genomic DNA from mouse tail (Nishiyama et al, 2007).…”

Section: Methodsmentioning

confidence: 99%

Reevaluation of Neurodegeneration inlurcherMice: Constitutive Ion Fluxes Cause Cell Death with, Not by, Autophagy

Nishiyama¹,

Matsuda²,

Kakegawa³

et al. 2010

J. Neurosci.

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The lurcher (Lc) mice have served as a valuable model for neurodegeneration for decades. Although the responsible mutation was identified in genes encoding ␦2 glutamate receptors (GluD2s), which are predominantly expressed in cerebellar Purkinje cells, how the mutant receptor (GluD2 Lc ) triggers cell death has remained elusive. Here, taking advantage of recent knowledge about the domain structure of GluD2, we reinvestigated Lc-mediated cell death, focusing on the "autophagic cell death" hypothesis. Although autophagy and cell death were induced by the expression of GluD2Lc in heterologous cells and cultured neurons, they were blocked by the introduction of mutations in the channel pore domain of GluD2Lc or by removal of extracellular Na ϩ . In addition, although GluD2 Lc is reported to directly activate autophagy, mutant channels that are not associated with n-PIST (neuronal isoform of protein-interacting specifically with TC10)-Beclin1 still caused autophagy and cell death. Furthermore, cells expressing GluD2Lc showed decreased ATP levels and increased AMP-activated protein kinase (AMPK) activities in a manner dependent on extracellular Na ϩ . Thus, constitutive currents were likely necessary and sufficient to induce autophagy via AMPK activation, regardless of the n-PIST-Beclin1 pathway in vitro. Interestingly, the expression of dominant-negative AMPK suppressed GluD2 Lc -induced autophagy but did not prevent cell death in heterologous cells. Similarly, the disruption of Atg5, a gene crucial for autophagy, did not prevent but rather aggravated Purkinje-cell death in Lc mice. Furthermore, calpains were specifically activated in Lc Purkinje cells. Together, these results suggest that Lc-mediated cell death was not caused by autophagy but necrosis with autophagic features both in vivo and in vitro.

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Section: Methodsmentioning

confidence: 99%

Reevaluation of Neurodegeneration inlurcherMice: Constitutive Ion Fluxes Cause Cell Death with, Not by, Autophagy

Nishiyama¹,

Matsuda²,

Kakegawa³

et al. 2010

J. Neurosci.

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“…Second, spines on distal dendrites are innervated exclusively by PFs in adult wild-type animals (Palay and Chan-Palay, 1974;Napper and Harvey, 1988), and the loss of GluR␦2 generates free spines on distal dendrites (Ichikawa et al, 2002). Third, viral transfer of GluR␦2 to adult GluR␦2-knock-out mice rapidly restores PF synapse formation in transfected PCs (Kakegawa et al, 2008(Kakegawa et al, , 2009). These results suggest that the primary role of GluR␦2 is to control and consolidate the connectivity of PF-PC synapses, which then suppresses aberrant extension and innervation by CFs.…”

Section: Glur␦2 Suppresses Distal Extension and Innervation By Ascendmentioning

confidence: 99%

“…Targeted disruption of GluR␦2 gene in mice causes mismatching between presynaptic and postsynaptic specializations and disconnection at PF-PC synapses (Guastavino et al, 1990;Kashiwabuchi et al, 1995;Kurihara et al, 1997;Lalouette et al, 2001). The N-terminal domain of GluR␦2 has been demonstrated to mediate PF-PC synaptogenesis by interacting neurexin through Cbln1 (Uemura et al, 2007(Uemura et al, , 2010; Kakegawa et al, 2008Kakegawa et al, , 2009Uemura and Mishina, 2008;Torashima et al, 2009;Matsuda et al, 2010). The loss of GluR␦2 further affects CF innervation; CFs extend distally to take over free spines of the target and neighboring PCs, causing multiple CF innervation (Hashimoto et al, 2001;Ichikawa et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Ablation of Glutamate Receptor GluRδ2 in Adult Purkinje Cells Causes Multiple Innervation of Climbing Fibers by Inducing Aberrant Invasion to Parallel Fiber Innervation Territory

Miyazaki¹,

Yamasaki²,

Takeuchi³

et al. 2010

J. Neurosci.

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Glutamate receptor GluR␦2 is exclusively expressed in Purkinje cells (PCs) from early development and plays key roles in parallel fiber (PF) synapse formation, elimination of surplus climbing fibers (CFs), long-term depression, motor coordination, and motor learning. To address its role in adulthood, we previously developed a mouse model of drug-induced GluR␦2 ablation in adult PCs (Takeuchi et al., 2005). In that study, we demonstrated an essential role to maintain the connectivity of PF-PC synapses, based on the observation that both mismatching of presynaptic and postsynaptic specializations and disconnection of PF-PC synapses are progressively increased after GluR␦2 ablation. Here, we pursued its role for CF wiring in adult cerebellum. In parallel with the disconnection of PF-PC synapses, ascending CF branches exhibited distal extension to innervate distal dendrites of the target and neighboring PCs. Furthermore, transverse CF branches, a short motile collateral rarely forming synapses in wild-type animals, displayed aberrant mediolateral extension to innervate distal dendrites of neighboring and remote PCs. Consequently, many PCs were wired by single main CF and other surplus CFs innervating a small part of distal dendrites. Electrophysiological recording further revealed that surplus CF-EPSCs characterized with slow rise time and small amplitude emerged after GluR␦2 ablation, and increased progressively both in number and amplitude. Therefore, GluR␦2 is essential for maintaining CF monoinnervation in adult cerebellum by suppressing aberrant invasion of CF branches to the territory of PF innervation. Thus, GluR␦2 fuels heterosynaptic competition and gives PFs the competitive advantages over CFs throughout the animal's life.

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“…On the one hand, EBC is impaired in mice with altered function or expression of mGluR1 (Aiba et al 1994;Kishimoto et al 2002;Ohtani et al 2014) or GluRd2 (GRID2) (Kishimoto et al 2001a,b;Kakegawa et al 2008), both of which are important for PF-PC LTD (Gao et al 2012). On the other hand, mice lacking PF-PC AMPA receptor suppression, a mechanism of LTD expression, show normal EBC (Schonewille et al 2011).…”

Section: Discussionmentioning

confidence: 99%

Cerebellar secretin modulates eyeblink classical conditioning

et al. 2014

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We have previously shown that intracerebellar infusion of the neuropeptide secretin enhances the acquisition phase of eyeblink conditioning (EBC). Here, we sought to test whether endogenous secretin also regulates EBC and to test whether the effect of exogenous and endogenous secretin is specific to acquisition. In Experiment 1, rats received intracerebellar infusions of the secretin receptor antagonist 5-27 secretin or vehicle into the lobulus simplex of cerebellar cortex immediately prior to sessions 1-3 of acquisition. Antagonist-infused rats showed a reduction in the percentage of eyeblink CRs compared with vehicle-infused rats. In Experiment 2, rats received intracerebellar infusions of secretin or vehicle immediately prior to sessions 1 -2 of extinction. Secretin did not significantly affect extinction performance. In Experiment 3, rats received intracerebellar infusions of 5-27 secretin or vehicle immediately prior to sessions 1 -2 of extinction. The secretin antagonist did not significantly affect extinction performance. Together, our current and previous results indicate that both exogenous and endogenous cerebellar secretin modulate acquisition, but not extinction, of EBC. We have previously shown that (1) secretin reduces surface expression of the voltage-gated potassium channel a-subunit Kv1.2 in cerebellar cortex and (2) intracerebellar infusions of a Kv1.2 blocker enhance EBC acquisition, much like secretin. Kv1.2 is almost exclusively expressed in cerebellar cortex at basket cell-Purkinje cell pinceaus and Purkinje cell dendrites; we propose that EBC-induced secretin release from PCs modulates EBC acquisition by reducing surface expression of Kv1.2 at one or both of these sites.Eyeblink conditioning (EBC) is a form of classical conditioning that is a powerful model for studying the underlying neural mechanisms of learning and memory. In EBC, an initially neutral conditioned stimulus (CS) is paired with an eyeblink-eliciting unconditioned stimulus (US).

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Differential Regulation of Synaptic Plasticity and Cerebellar Motor Learning by the C-Terminal PDZ-Binding Motif of GluRδ2

Cited by 84 publications

References 40 publications

Reevaluation of Neurodegeneration inlurcherMice: Constitutive Ion Fluxes Cause Cell Death with, Not by, Autophagy

Reevaluation of Neurodegeneration inlurcherMice: Constitutive Ion Fluxes Cause Cell Death with, Not by, Autophagy

Ablation of Glutamate Receptor GluRδ2 in Adult Purkinje Cells Causes Multiple Innervation of Climbing Fibers by Inducing Aberrant Invasion to Parallel Fiber Innervation Territory

Cerebellar secretin modulates eyeblink classical conditioning

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