Disruption of Slc4a10 augments neuronal excitability and modulates synaptic short-term plasticity

Sinning, Anne; Liebmann, Lutz; Hübner, Christian A.

doi:10.3389/fncel.2015.00223

Cited by 27 publications

(18 citation statements)

References 51 publications

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“…Within the excitatory post-synaptic compartment, SHANK2 is a post-synaptic scaffolding protein and GRIA2 is glutamate ionotropic receptor AMPA type subunit, both of which mediate excitatory neurotransmission 52,53 . Also in the post-synaptic compartment, SLC4A10 is associated with sodium channels in principal and inhibitory neurons 54 . These data demonstrate that acute HA manipulation for 24h has immediate and detectable effects on synapse-associated transcripts.…”

Section: Resultsmentioning

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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Section: Resultsmentioning

confidence: 99%

Hyaluronan regulates synapse formation and function in developing neural networks

Wilson

Knudson

Litwa

2020

Sci Rep

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“…SLC4A1 encodes for a member of the ion transporter SLC4 family, that mediate the pH regulation and transepithelial ion transport, critical for several biological processes, including modulation of neuronal excitability [57,58,59,60]. Dysfunctions of SLC4 transporters are associated with a broad range of diseases, including central nervous system disorders, such as intellectual disability, migraine, epilepsy, autism and drug addiction [61,62,63,64,65,66].…”

Section: Discussionmentioning

confidence: 99%

Analysis of a Sardinian Multiplex Family with Autism Spectrum Disorder Points to Post-Synaptic Density Gene Variants and Identifies CAPG as a Functionally Relevant Candidate Gene

Bacchelli

Loi

Cameli

et al. 2019

JCM

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Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders with high heritability, although their underlying genetic factors are still largely unknown. Here we present a comprehensive genetic characterization of two ASD siblings from Sardinia by genome-wide copy number variation analysis and whole exome sequencing (WES), to identify novel genetic alterations associated with this disorder. Single nucleotide polymorphism (SNP) array data revealed a rare microdeletion involving CAPG, ELMOD3, and SH2D6 genes, in both siblings. CAPG encodes for a postsynaptic density (PSD) protein known to regulate spine morphogenesis and synaptic formation. The reduced CAPG mRNA and protein expression levels in ASD patients, in the presence of hemizygosity or a particular genetic and/or epigenetic background, highlighted the functional relevance of CAPG as a candidate gene for ASD. WES analysis led to the identification in both affected siblings of a rare frameshift mutation in VDAC3, a gene intolerant to loss of function mutation, encoding for a voltage-dependent anion channel localized on PSD. Moreover, four missense damaging variants were identified in genes intolerant to loss of function variation encoding for PSD proteins: PLXNA2, KCTD16, ARHGAP21, and SLC4A1. This study identifies CAPG and VDAC3 as candidate genes and provides additional support for genes encoding PSD proteins in ASD susceptibility.

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“…Lowered seizure thresholds in some strains of ABT-null mice suggest that ABTs may be potential targets for anticonvulsant therapy. However, the need for caution is shown by the observation that, at least in the case of NBCn2-null mice, a reduced seizure-threshold does not mean reduced neuronal excitability [122] . The role of ABTs and CAs in CSF secretion hints at the potential for targeting of these proteins to lower intracranial pressure in idiopathic intracranial hypertension (IIH).…”

Section: Applications By Organ Systemmentioning

confidence: 99%

The therapeutic importance of acid-base balance

Quade

Parker

Occhipinti

2021

Biochemical Pharmacology

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Baking soda and vinegar have been used as home remedies for generations and today we are only a mouse-click away from claims that baking soda, lemon juice, and apple cider vinegar are miracles cures for everything from cancer to COVID-19. Despite these specious claims, the therapeutic value of controlling acid-base balance is indisputable and is the basis of Food and Drug Administration-approved treatments for constipation, epilepsy, metabolic acidosis, and peptic ulcers. In this narrative review, we present evidence in support of the current and potential therapeutic value of countering local and systemic acid-base imbalances, several of which do in fact involve the administration of baking soda (sodium bicarbonate). Furthermore, we discuss the side effects of pharmaceuticals on acid-base balance as well as the influence of acid-base status on pharmacokinetic properties of drugs. Our review considers all major organs systems as well as information relevant to several clinical specialties such as anesthesiology, infectious disease, oncology, dentistry, and surgery.

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Disruption of Slc4a10 augments neuronal excitability and modulates synaptic short-term plasticity

Cited by 27 publications

References 51 publications

Hyaluronan regulates synapse formation and function in developing neural networks

Hyaluronan regulates synapse formation and function in developing neural networks

Analysis of a Sardinian Multiplex Family with Autism Spectrum Disorder Points to Post-Synaptic Density Gene Variants and Identifies CAPG as a Functionally Relevant Candidate Gene

The therapeutic importance of acid-base balance

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