Hyaluronan synthesis supports glutamate transporter activity

Hayashi, Mariko; Nishioka, Tomoki; Shimizu, Hideo; Takahashi, Kanako; Kakegawa, Wataru; Mikami, Tetsuri; Hirayama, Yuri; Koizumi, Schuichi; Yuzaki, Michisuke; Tammi, Markku; Sekino, Yuko; Kaibuchi, Kozo; Shigemoto-Mogami, Yukari; Yasui, Masato; Sato, Kaoru

doi:10.1111/jnc.14791

Cited by 6 publications

(5 citation statements)

References 57 publications

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“…Astrocytes contribute to synaptic function in part by regulating glutamate uptake from the synaptic cleft, preventing glutamate-induced neurotoxicity [58,59]. Hyaluronan supports the activity of the glial glutamate transporter [60]. Thus, while our data supports a model in which HA is directly synthesized into the developing synaptic cleft, it is interesting to speculate that with further development, HA is synthesized by associated astrocytes, which would surround and stabilize mature synaptic contacts.…”

Section: Discussionmentioning

confidence: 50%

Synaptic Hyaluronan Synthesis and CD44-Mediated Signaling Coordinate Neural Circuit Development

Wilson

Litwa

2021

Cells

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The hyaluronan-based extracellular matrix is expressed throughout nervous system development and is well-known for the formation of perineuronal nets around inhibitory interneurons. Since perineuronal nets form postnatally, the role of hyaluronan in the initial formation of neural circuits remains unclear. Neural circuits emerge from the coordinated electrochemical signaling of excitatory and inhibitory synapses. Hyaluronan localizes to the synaptic cleft of developing excitatory synapses in both human cortical spheroids and the neonatal mouse brain and is diminished in the adult mouse brain. Given this developmental-specific synaptic localization, we sought to determine the mechanisms that regulate hyaluronan synthesis and signaling during synapse formation. We demonstrate that hyaluronan synthase-2, HAS2, is sufficient to increase hyaluronan levels in developing neural circuits of human cortical spheroids. This increased hyaluronan production reduces excitatory synaptogenesis, promotes inhibitory synaptogenesis, and suppresses action potential formation. The hyaluronan receptor, CD44, promotes hyaluronan retention and suppresses excitatory synaptogenesis through regulation of RhoGTPase signaling. Our results reveal mechanisms of hyaluronan synthesis, retention, and signaling in developing neural circuits, shedding light on how disease-associated hyaluronan alterations can contribute to synaptic defects.

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Section: Discussionmentioning

confidence: 50%

Synaptic Hyaluronan Synthesis and CD44-Mediated Signaling Coordinate Neural Circuit Development

Wilson

Litwa

2021

Cells

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“…We found that the colocalization of the three proteins is significantly increased in BD (3-way ANOVA, p = 0.0188, Figure 7D), further supporting an upregulation of SPP1-CD44 signalling in BD astrocytes. In light of our transcriptomic and IHC results, this upregulated communication appreas to be implicated in BD and could be contributing to the downregulated immune responses in astrocytes 87 and dysfunctional glutamate homeostasis 88 .…”

Section: Resultsmentioning

confidence: 75%

Altered astrocytic and microglial homeostasis characterizes a decreased proinflammatory state in bipolar disorder

Amossé,

Tournier,

Badina

et al. 2023

Preprint

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Multiple lines of evidence point to peripheral immune alterations in bipolar disorder (BD) although the activity of brain immune mechanisms remain largely unexplored. To identify the cell type-specific immune alterations in the BD brain, we performed a proteomic and single nuclear transcriptomic analysis ofpostmortemcingulate cortex samples from BD and control subjects. Our results showed that genes associated to the genetic risk for BD are enriched in microglia and astrocytes. Transcriptomic alterations in microglia point to a reduced proinflammatory phenotype, associated to reduced resistance to oxidative stress and apoptosis, which was confirmed with immunohistochemical quantification of IBA1 density. Astrocytes show transcriptomic evidence of an imbalance of multiple metabolic pathways, extracellular matrix composition and downregulated immune signalling. These alterations are associated toADCY2andNCAN,two GWAS genes upregulated in astrocytes. Finally, cell-cell communication analysis prioritized upregulated SPP1-CD44 signalling to astrocytes as a potential regulator of the transcriptomic alterations in BD. Our results indicate that microglia and astrocytes are characterized by downregulated immune responses associated to a dysfunction of core mechanisms via which these cells contribute to brain homeostasis.

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“…By expressing both hyaluronidase and MMPs, astrocytes play an important role in hyaluronan synthesis and catabolism ( Muir et al, 2002 ; Al’Qteishat et al, 2006 ). HA in turn regulates the morphology of astrocytes and proper trafficking and function of glutamate transporters by CD44-evoked Rac1 signaling ( Hayashi et al, 2019 ; Peters and Sherman, 2020 ).…”

Section: Homeostatic Regulation Of Extracellular Matrix and Perineuro...mentioning

confidence: 99%

A glial perspective on the extracellular matrix and perineuronal net remodeling in the central nervous system

Tewari

Chaunsali

Prim

et al. 2022

Front. Cell. Neurosci.

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A structural scaffold embedding brain cells and vasculature is known as extracellular matrix (ECM). The physical appearance of ECM in the central nervous system (CNS) ranges from a diffused, homogeneous, amorphous, and nearly omnipresent matrix to highly organized distinct morphologies such as basement membranes and perineuronal nets (PNNs). ECM changes its composition and organization during development, adulthood, aging, and in several CNS pathologies. This spatiotemporal dynamic nature of the ECM and PNNs brings a unique versatility to their functions spanning from neurogenesis, cell migration and differentiation, axonal growth, and pathfinding cues, etc., in the developing brain, to stabilizing synapses, neuromodulation, and being an active partner of tetrapartite synapses in the adult brain. The malleability of ECM and PNNs is governed by both intrinsic and extrinsic factors. Glial cells are among the major extrinsic factors that facilitate the remodeling of ECM and PNN, thereby acting as key regulators of diverse functions of ECM and PNN in health and diseases. In this review, we discuss recent advances in our understanding of PNNs and how glial cells are central to ECM and PNN remodeling in normal and pathological states of the CNS.

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Hyaluronan synthesis supports glutamate transporter activity

Cited by 6 publications

References 57 publications

Synaptic Hyaluronan Synthesis and CD44-Mediated Signaling Coordinate Neural Circuit Development

Synaptic Hyaluronan Synthesis and CD44-Mediated Signaling Coordinate Neural Circuit Development

Altered astrocytic and microglial homeostasis characterizes a decreased proinflammatory state in bipolar disorder

A glial perspective on the extracellular matrix and perineuronal net remodeling in the central nervous system

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