Brain extracellular space, hyaluronan, and the prevention of epileptic seizures

Perkins, Katherine L.; Arranz, Amaia M.; Yamaguchi, Yu; Hrabětová, Sabina

doi:10.1515/revneuro-2017-0017

Cited by 45 publications

(58 citation statements)

References 215 publications

(305 reference statements)

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“…So far, we have applied SUSHI only to brain slices, but it should also work in the intact brain by adapting cranial window approaches and 3D-STED microscopy in vivo (Pfeiffer et al, 2018), the main limitations being imaging depth and brain motion. The use of adaptive optics (Gould et al, 2012;Patton et al, 2016) and 2-photon STED microscopy (Bethge et al, 2013;Takasaki et al, 2013) as well as optimized surgery and labeling techniques are bound to help overcome these hurdles.…”

Section: Sushimentioning

confidence: 99%

Unveiling the Extracellular Space of the Brain: From Super-resolved Microstructure toIn VivoFunction

et al. 2018

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The extracellular space occupies approximately one-fifth of brain volume, molding a spider web of gaps filled with interstitial fluid and extracellular matrix where neurons and glial cells perform in concert. Yet, very little is known about the spatial organization and dynamics of the extracellular space, let alone its influence on brain function, owing to a lack of appropriate techniques (and a traditional bias toward the inside of cells, not the spaces in between). At the same time, it is clear that understanding fundamental brain functions, such as synaptic transmission, memory, sleep, and recovery from disease, calls for more focused research on the extracellular space of the brain. This review article highlights several key research areas, covering recent methodological and conceptual progress that illuminates this understudied, yet critically important, brain compartment, providing insights into the opportunities and challenges of this nascent field.

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Section: Sushimentioning

confidence: 99%

Unveiling the Extracellular Space of the Brain: From Super-resolved Microstructure toIn VivoFunction

et al. 2018

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“…These supramolecular HA-proteoglycan complexes are responsible for maintaining space and structure through extensive interactions with water. HA-proteoglycan complexes are capable of binding three layers of water molecules around them 16 . In addition to its spatial properties, this meshwork interacts with other ECM components, such as collagen, Tenascin C, fibronectin, and laminin 15 .…”

Section: Introductionmentioning

confidence: 99%

“…A conditional knockout mouse for Hyaluronan Synthase 2 (HAS2) significantly decreases HA levels in the cortex, resulting in epileptic seizures 12 . Similarly, HA removal via hyaluronidase injection into the right lateral ventricle of cat brains results in epileptiform activity 16 . Hyperexcitability of neural networks is characteristic of the neurodevelopmental disorders of epilepsy, intellectual disability, and autism spectrum disorders 26 – 28 .…”

Section: Introductionmentioning

confidence: 99%

Hyaluronan regulates synapse formation and function in developing neural networks

Wilson

Knudson

Litwa

2020

Sci Rep

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Neurodevelopmental disorders present with synaptic alterations that disrupt the balance between excitatory and inhibitory signaling. For example, hyperexcitability of cortical neurons is associated with both epilepsy and autism spectrum disorders. However, the mechanisms that initially establish the balance between excitatory and inhibitory signaling in brain development are not well understood. Here, we sought to determine how the extracellular matrix directs synapse formation and regulates synaptic function in a model of human cortical brain development. The extracellular matrix, making up twenty percent of brain volume, is largely comprised of hyaluronan. Hyaluronan acts as both a scaffold of the extracellular matrix and a space-filling molecule. Hyaluronan is present from the onset of brain development, beginning with neural crest cell migration. Through acute perturbation of hyaluronan levels during synaptogenesis, we sought to determine how hyaluronan impacts the ratio of excitatory to inhibitory synapse formation and the resulting neural activity. We used 3-D cortical spheroids derived from human induced pluripotent stem cells to replicate this neurodevelopmental window. Our results demonstrate that hyaluronan preferentially surrounds nascent excitatory synapses. Removal of hyaluronan increases the expression of excitatory synapse markers and results in a corresponding increase in the formation of excitatory synapses, while also decreasing inhibitory synapse formation. This increased excitatory synapse formation elevates network activity, as demonstrated by microelectrode array analysis. In contrast, the addition of purified hyaluronan suppresses excitatory synapse formation. These results establish that the hyaluronan extracellular matrix surrounds developing excitatory synapses, where it critically regulates synapse formation and the resulting balance between excitatory to inhibitory signaling.

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“…Under different osmotic conditions, signaling process modulated by integrin-ECM contacts is either activated or inhibited. As observed in the SON, hyperosmotic stress caused by increasing NaCl concentration can decrease polysialic acid-neural cell adhesion molecule complex content (Schmelzer and Miller, 2002 ) and increases extracellular volume (Perkins et al, 2017 ). The changes in the astrocytic ECM (Pierre et al, 2001 ) could further activate astrocytic TRP channels through integrins (Song and Dityatev, 2018 ).…”

Section: Osmosensation By Astrocytesmentioning

confidence: 99%

Astroglial Modulation of Hydromineral Balance and Cerebral Edema

Wang

Parpura

2018

Front. Mol. Neurosci.

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Maintenance of hydromineral balance (HB) is an essential condition for life activity at cellular, tissue, organ and system levels. This activity has been considered as a function of the osmotic regulatory system that focuses on hypothalamic vasopressin (VP) neurons, which can reflexively release VP into the brain and blood to meet the demand of HB. Recently, astrocytes have emerged as an essential component of the osmotic regulatory system in addition to functioning as a regulator of the HB at cellular and tissue levels. Astrocytes express all the components of osmoreceptors, including aquaporins, molecules of the extracellular matrix, integrins and transient receptor potential channels, with an operational dynamic range allowing them to detect and respond to osmotic changes, perhaps more efficiently than neurons. The resultant responses, i.e., astroglial morphological and functional plasticity in the supraoptic and paraventricular nuclei, can be conveyed, physically and chemically, to adjacent VP neurons, thereby influencing HB at the system level. In addition, astrocytes, particularly those in the circumventricular organs, are involved not only in VP-mediated osmotic regulation, but also in regulation of other osmolality-modulating hormones, including natriuretic peptides and angiotensin. Thus, astrocytes play a role in local/brain and systemic HB. The adaptive astrocytic reactions to osmotic challenges are associated with signaling events related to the expression of glial fibrillary acidic protein and aquaporin 4 to promote cell survival and repair. However, prolonged osmotic stress can initiate inflammatory and apoptotic signaling processes, leading to glial dysfunction and a variety of brain diseases. Among many diseases of brain injury and hydromineral disorders, cytotoxic and osmotic cerebral edemas are the most common pathological manifestation. Hyponatremia is the most common cause of osmotic cerebral edema. Overly fast correction of hyponatremia could lead to central pontine myelinolysis. Ischemic stroke exemplifies cytotoxic cerebral edema. In this review, we summarize and analyze the osmosensory functions of astrocytes and their implications in cerebral edema.

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Brain extracellular space, hyaluronan, and the prevention of epileptic seizures

Cited by 45 publications

References 215 publications

Unveiling the Extracellular Space of the Brain: From Super-resolved Microstructure toIn VivoFunction

Unveiling the Extracellular Space of the Brain: From Super-resolved Microstructure toIn VivoFunction

Hyaluronan regulates synapse formation and function in developing neural networks

Astroglial Modulation of Hydromineral Balance and Cerebral Edema

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