Postsynaptic Modulation of AMPA Receptor-Mediated Synaptic Responses and LTP by the Type 3 Ryanodine Receptor

doi:10.1006/mcne.2001.0981

Molecular and Cellular Neuroscience

Volume 17, Issue 5, May 2001, Pages 921-930

https://doi.org/10.1006/mcne.2001.0981 Get rights and content

Abstract

The precise function of ryanodine receptors (RyRs) in synaptic transmission is unknown, but three of their subtypes are expressed in the brain. We examined the roleof RyRs in excitatory synaptic transmission in hippocampalslices, using type 3 RyR (RyR3)-deficient mice. The α-amino-3-hydroxy-5-methyl-4-isoxozolepropionic acid (AMPA) receptor-mediated basal synaptic responses in the CA1 region of mutant mice were smaller than those of wild-type mice, while there wasno difference in N-methyl- $d$ -aspartate receptor-mediated responses, suggesting selective postsynaptic modification of AMPA receptors by RyR3. The expression of synaptic AMPA receptor subunits examined by Western blotting or immunohistochemistry was indistinguishable,suggesting that the smaller AMPA synaptic responses in mutant mice were not due tothe reduced number of synaptic AMPA receptors. Although the initial potentiation following tetanic stimulation of afferent fibers was similar, long-term potentiation (LTP) was smaller in mutant mice. There were no differences in presynaptic electrophysiological properties. We thus conclude that RyR3 postsynaptically regulates the properties of AMPA receptors and LTP.

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Yet, other reports indicate that RyR3 deficient mice display successful learning behavior but impaired ability to relearn a new target [15], and exhibit deficits in contextual fear conditioning [16]. It has been reported, in addition, that RyR3 channels are engaged in LTP, and the postsynaptic modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor-mediated synaptic responses [17]. Subsequent studies have reported that RyR3-mediated CICR controls the slow after-hyperpolarization current in CA1 pyramidal neurons of mouse hippocampus [18], and that activation of RyR3 channels and of the extracellular signal-regulated kinase (ERK) mediates superoxide-induced potentiation in the hippocampus [19].
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SDS-PAGE and immunoblotting were performed as described previously (Hozumi et al., 2008). The following antibodies were used: Gαq/11 (0.5 μg/ml; sc-392; Santa Cruz Biotechnology Inc., Santa Cruz, CA), mGluR5 (0.5 μg/ml) (Uchigashima et al., 2007), PLCβ1 (0.5 μg/ml) (Fukaya et al., 2008), PSD-95 (0.5 μg/ml) (Fukaya and Watanabe, 2000), Homer1 (0.5 μg/ml) (Nakamura et al., 2004), TARP γ-8 (0.5 μg/ml) (Fukaya et al., 2006), GluA1 (0.5 μg/ml) (Shimuta et al., 2001), GluA2 (0.5 μg/ml) (Shimuta et al., 2001), and β-actin (1:5000; A5441; Sigma-Aldrich Co., Saint Louis, MO) antibodies. Signal intensities of immunoreaction were determined digitally using the densitometry function of ImageJ software and normalized with β-actin.
Spine formation, a salient feature underlying neuronal plasticity to adapt to a changing environment, is regulated by complex machinery involving membrane signal transduction. The diacylglycerol kinase (DGK) family, which is involved in membrane lipid metabolism, catalyzes the phosphorylation of a lipid second messenger, diacylglycerol (DG). Of the DGKs, DGKβ is characterized by predominant expression in a specific brain region: the striatum. We previously demonstrated that DGKβ is expressed selectively in medium spiny neurons (MSNs) and that it is highly enriched in the perisynaptic membrane on dendritic spines contacted with excitatory terminals. Moreover, DGKβ regulates spinogenesis through actin-based remodeling in an activity-dependent manner. However, the detailed mechanisms of spinogenesis regulation and its functional significance remain unclear. To address these issues, we performed Golgi–Cox staining to examine morphological aspects of MSNs in the striatum of DGKβ-knockout (KO) mice. Results show that striatal MSNs of DGKβ-KO mice exhibited lower dendritic spine density at distal dendrites than wild-type mice did. We also sought protein targets that interact with DGKβ and identified the GluA2 AMPA receptor subunit as a novel DGKβ binding partner. In addition, DGKβ-deficient brain exhibits significant reduction of TARP γ-8, which represents a transmembrane AMPA receptor regulatory protein. These findings suggest that DGKβ regulates the spine formation at distal dendrites in MSNs.
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Although little is known about the role of RyR within neuronal tissue, RyR3 has canonically been viewed as the major isoform of the brain while RyR1 and RyR2 are also expressed [59,60]. Although the specific RyR isoform responsible for ER Ca2+ release has not been clarified for the numerous neuronal cell subtypes in the brain, it is hypothesized that RyR isoforms may be neuronal subtype-specific [61,62]. In addition, recent evidence has suggested that neuronal LTCCs may couple with RyR1 in a manner analogous to voltage-triggered RyR1 opening in skeletal muscle.
Excitable tissues rely on junctional membrane complexes to couple cell surface signals to intracellular channels. The junctophilins have emerged as a family of proteins critical in coordinating the maturation and maintenance of this cellular ultrastructure. Within skeletal and cardiac muscle, junctophilin 1 and junctophilin 2, respectively, couple sarcolemmal and intracellular calcium channels. In neuronal tissue, junctophilin 3 and junctophilin 4 may have an emerging role in coupling membrane neurotransmitter receptors and intracellular calcium channels. These important physiological roles are highlighted by the pathophysiology which results when these proteins are perturbed, and a growing body of literature has associated junctophilins with the pathogenesis of human disease.
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In neurons, extracellular calcium entry occurs through plasma membrane channels such as NMDA receptors and voltage-gated calcium channels (VGCC), whereas intracellular calcium are released from the ER through the IP3 receptor (IP3R) or RyR. Ca2+ released from internal stores enhances and dynamically regulates cytosolic Ca2+ levels, which may be involved in synaptic plasticity and memory (Unni et al., 2004; Adasme et al., 2011), presynaptic transmitter release (Zhang et al., 2009), and postsynaptic functions (Shimuta et al., 2001; Goussakov et al., 2010). RyR is coded by three genes, namely, RyR1, RyR2, and RyR3, which have different expression patterns in the brain.
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¹: To whom correspondence and reprint requests should be addressed at Department of Physiology, Kobe University School of Medicine, Kobe 650-0017 Japan. Fax: +81 78 382 5379. E-mail: [email protected].

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Regular ArticlePostsynaptic Modulation of AMPA Receptor-Mediated Synaptic Responses and LTP by the Type 3 Ryanodine Receptor

Abstract

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Characterization of Ca2+ signals induced in hippocampal CA1 neurones by the synaptic activation of NMDA receptors

J. Physiol.

Deletion of the ryanodine receptor type 3 (RyR3) impairs forms of synaptic plasticity and spatial learning

EMBO J.

Regulatory phosphorylation of AMPA-type glutamate receptors by CaM-KII during long-term potentiation

Science

Induction of LTP in the hippocampus needs synaptic activation of glutamate metabotropic receptors

Nature

NMDA and non-NMDA receptors are co-localized at individual excitatory synapses in cultured rat hippocampus

Nature

Modulation of AMPA receptor unitary conductance by synaptic activity

Nature

Inositol trisphosphate and calcium signalling

Nature

A synaptic model of memory: Long-term potentiation in the hippocampus

Nature

A molecular switch activated by metabotropic glutamate receptors regulates induction of long-term potentiation

Nature

Isolation and characterization of postsynaptic densities from various brain regions: Enrichment of different types of postsynaptic densities

J. Cell Biol.

(RS)-α-Methyl-4-carboxyphenylglycine neither prevents induction of LTP nor antagonizes metabotropic glutamate receptors in CA1 hippocampal neurons

J. Neurophysiol.

Ca2+/calmodulin-kinase II enhances channel conductance of α-amino-3-hydroxy-5-methyl-4-isoxazolepropinate type glutamate receptors

Proc. Natl. Acad. Sci. USA

Regular Article
Postsynaptic Modulation of AMPA Receptor-Mediated Synaptic Responses and LTP by the Type 3 Ryanodine Receptor

Characterization of Ca²⁺ signals induced in hippocampal CA1 neurones by the synaptic activation of NMDA receptors

Ca²⁺/calmodulin-kinase II enhances channel conductance of α-amino-3-hydroxy-5-methyl-4-isoxazolepropinate type glutamate receptors