Chondroitin Sulfate Proteoglycan Tenascin-R Regulates Glutamate Uptake by Adult Brain Astrocytes

Okuda, Hiromichi; Tatsumi, Kouko; Morita, Shoko; Shibukawa, Yoshiyuki; Korekane, Hiroaki; Horii-Hayashi, Noriko; Wada, Yoshinao; Taniguchi, Naoyuki; Wanaka, Akio

doi:10.1074/jbc.m113.504787

Cited by 29 publications

(30 citation statements)

References 59 publications

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“…Although GS is widely considered to be astrocyte-specific (Armbruster et al, 2016; Habbas et al, 2015; Okuda et al, 2014; Papageorgiou et al, 2018; Theofilas et al, 2017; Tong et al, 2014), there have been reports of GS expression, particularly at the mRNA level, in oligodendrocyte progenitors and microglia (Nakajima et al, 2017; Palmieri et al, 2017; Zhang et al, 2014). Within the ventral midbrain of naive young adult mice, we did not detect expression of GS mRNA or protein in these cell types.…”

Section: Discussionmentioning

confidence: 99%

“…Currently, astrocytes are considered the sole glial cell type that contributes to glutamate uptake and degradation in the CNS (Jayakumar and Norenberg, 2016; Liang et al, 2006; Ortinski et al, 2010; Papageorgiou et al, 2018; Schousboe et al, 2013; Schousboe, 2019; Sun et al, 2017; Tani et al, 2014; Trabelsi et al, 2017; Yuan et al, 2017), as they express high levels of glutamate transporters and glutamine synthetase (GS), an enzyme that converts glutamate into glutamine. In keeping with this view, GS is frequently used as an astrocyte-specific marker (Armbruster et al, 2016; Habbas et al, 2015; Okuda et al, 2014; Papageorgiou et al, 2018; Theofilas et al, 2017; Tong et al, 2014). However, GS expression has also been reported in oligodendrocytes (Bernstein et al, 2014; Takasaki et al, 2010), glial cells known for producing myelin and ensheathing axons in the CNS (Pan and Chan, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Oligodendrocytes Support Neuronal Glutamatergic Transmission via Expression of Glutamine Synthetase

et al. 2019

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SUMMARY Glutamate has been implicated in a wide range of brain pathologies and is thought to be metabolized via the astrocyte-specific enzyme glutamine synthetase (GS). We show here that oligodendrocytes, the myelinating glia of the central nervous system, also express high levels of GS in caudal regions like the midbrain and the spinal cord. Selective removal of oligodendrocyte GS in mice led to reduced brain glutamate and glutamine levels and impaired glutamatergic synaptic transmission without disrupting myelination. Furthermore, animals lacking oligodendrocyte GS displayed deficits in cocaine-induced locomotor sensitization, a behavior that is dependent on glutamatergic signaling in the midbrain. Thus, oligodendrocytes support glutamatergic transmission through the actions of GS and may represent a therapeutic target for pathological conditions related to brain glutamate dysregulation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Oligodendrocytes Support Neuronal Glutamatergic Transmission via Expression of Glutamine Synthetase

et al. 2019

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“…The ECM acts as a passive diffusion barrier for cell surface molecules, including neurotransmitter receptors, and thus, it contributes to the definition of plasma membrane functional domains. Several ECM components, including tenascin-R (Tnr), neurocan, versican, phosphacan, brevican, Crtl1, Bral2, and HAPLN3, are expressed in a glia-dependent manner (Okuda et al, 2014;Dzyubenko et al, 2016), whereas aggrecan expression is neuron-dependent, and hyaluronic acid (HA) synthesis is both neuron-and glia-dependent (Dityatev & Fellin, 2008). Several ECM components, including tenascin-R (Tnr), neurocan, versican, phosphacan, brevican, Crtl1, Bral2, and HAPLN3, are expressed in a glia-dependent manner (Okuda et al, 2014;Dzyubenko et al, 2016), whereas aggrecan expression is neuron-dependent, and hyaluronic acid (HA) synthesis is both neuron-and glia-dependent (Dityatev & Fellin, 2008).…”

Section: Introductionmentioning

confidence: 99%

Pentraxin 3 regulates synaptic function by inducing AMPA receptor clustering via ECM remodeling and β1‐integrin

et al. 2018

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Control of synapse number and function in the developing central nervous system is critical to the formation of neural circuits. Astrocytes play a key role in this process by releasing factors that promote the formation of excitatory synapses. Astrocyte‐secreted thrombospondins (TSPs) induce the formation of structural synapses, which however remain post‐synaptically silent, suggesting that completion of early synaptogenesis may require a two‐step mechanism. Here, we show that the humoral innate immune molecule Pentraxin 3 (PTX3) is expressed in the developing rodent brain. PTX3 plays a key role in promoting functionally‐active CNS synapses, by increasing the surface levels and synaptic clustering of AMPA glutamate receptors. This process involves tumor necrosis factor‐induced protein 6 (TSG6), remodeling of the perineuronal network, and a β1‐integrin/ERK pathway. Furthermore, PTX3 activity is regulated by TSP1, which directly interacts with the N‐terminal region of PTX3. These data unveil a fundamental role of PTX3 in promoting the first wave of synaptogenesis, and show that interplay of TSP1 and PTX3 sets the proper balance between synaptic growth and synapse function in the developing brain.

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“…Parvalbumin‐positive GABAergic neurons are frequently associated with preineuronal nets (Härtig et al ; Yamada and Jinno ) and also express excitatory amino‐acid carrier 1 subtype of glutamate transporters (Holmseth et al ). In astrocytes, knockdown of tenascin R, a perineuronal nets component, reduces glutamate uptake through downregulation of GLAST (Okuda et al ). These evidences indicate that perineuronal nets may affect expression and/or stability of glutamate transporters through regulation of hyaluronan synthesis or degradation.…”

Section: Discussionmentioning

confidence: 99%

Hyaluronan synthesis supports glutamate transporter activity

Hayashi

Nishioka

Shimizu

et al. 2019

Journal of Neurochemistry

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Hyaluronan is synthesized, secreted, and anchored by hyaluronan synthases (HAS) at the plasma membrane and comprises the backbone of perineuronal nets around neuronal soma and dendrites. However, the molecular targets of hyaluronan to regulate synaptic transmission in the central nervous system have not been fully identified. Here, we report that hyaluronan is a negative regulator of excitatory signals. At excitatory synapses, glutamate is removed by glutamate transporters to turn off the signal and prevent excitotoxicity. Hyaluronan synthesized by HAS supports the activity of glial glutamate transporter 1 (GLT1). GLT1 also retracted from cellular processes of cultured astrocytes after hyaluronidase treatment and hyaluronan synthesis inhibition. A serial knockout study showed that all three HAS subtypes recruit GLT1 to cellular processes. Furthermore, hyaluronidase treatment activated neurons in a dissociated rat hippocampal culture and caused neuronal damage due to excitotoxicity. Our findings reveal that hyaluronan helps to turn off excitatory signals by supporting glutamate clearance. Cover Image for this issue: doi: .

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Chondroitin Sulfate Proteoglycan Tenascin-R Regulates Glutamate Uptake by Adult Brain Astrocytes

Cited by 29 publications

References 59 publications

Oligodendrocytes Support Neuronal Glutamatergic Transmission via Expression of Glutamine Synthetase

Oligodendrocytes Support Neuronal Glutamatergic Transmission via Expression of Glutamine Synthetase

Pentraxin 3 regulates synaptic function by inducing AMPA receptor clustering via ECM remodeling and β1‐integrin

Hyaluronan synthesis supports glutamate transporter activity

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