Autism spectrum disorder traits in<i>Slc9a9</i>knock‐out mice

Yang, Lina; Faraone, Stephen V.; Zhang‐James, Yanli

doi:10.1002/ajmg.b.32415

Cited by 20 publications

(25 citation statements)

References 85 publications

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“…Receptor-mediated endocytosis of holo-transferrin is the canonical physiological mode of iron delivery to cells (2). Electrochemical potential (E 0 ) of transferrin iron complex is too negative, and acidification of endosomal lumen has been sug- MARCH 10, 2017 • VOLUME 292 • NUMBER 10 gested to make the E 0 more positive (29). Thus, a drop in the pH caused by proton influx via V-ATPase in the sorting endosomes could lead to release of iron from holo-transferrin-TfR complex.…”

Section: Discussionmentioning

confidence: 99%

“…Functional evaluation of these autismassociated mutations in astrocytes showed that these cells lose their ability to clear glutamate to a significant extent as a consequence of dysregulated trafficking of glutamate transporter (GLAST) (27). Moreover, global knock-out SLC9A9 mice (Slc9a9 KO) show traits of autism spectrum and attention deficit hyperactivity disorder (29). Thus, by modulating endosomal pH, NHE9 could regulate delivery and recycling of various endocytic cargos, including proteins involved in iron homeostasis.…”

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confidence: 99%

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Na+/H+ Exchanger 9 Regulates Iron Mobilization at the Blood-Brain Barrier in Response to Iron Starvation

Beydoun¹,

Hamood²,

Zubieta

et al. 2017

Journal of Biological Chemistry

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Edited by Paul E. FraserIron is essential for brain function, with loss of iron homeostasis in the brain linked to neurological diseases ranging from rare syndromes to more common disorders, such as Parkinson's and Alzheimer's diseases. Iron entry into the brain is regulated by the blood-brain barrier (BBB). Molecular mechanisms regulating this transport are poorly understood. Using an in vitro model of the BBB, we identify NHE9, an endosomal cation/proton exchanger, as a novel regulator of this system. Human brain microvascular endothelial cells (hBMVECs) that constitute the BBB receive brain iron status information via paracrine signals from ensheathing astrocytes. In hBMVECs, we show that NHE9 expression is up-regulated very early in a physiological response invoked by paracrine signals from iron-starved astrocytes. Ectopic expression of NHE9 in hBMVECs without external cues induced up-regulation of the transferrin receptor (TfR) and down-regulation of ferritin, leading to an increase in iron uptake. Mechanistically, we demonstrate that NHE9 localizes to recycling endosomes in hBMVECs where it raises the endosomal pH. The ensuing alkalization of the endosomal lumen increased translocation of TfRs to the hBMVEC membrane. TfRs on the membrane were previously shown to facilitate both recycling-dependent and -independent iron uptake. We propose that NHE9 regulates TfR-dependent, recycling-independent iron uptake in hBMVECs by fine-tuning the endosomal pH in response to paracrine signals and is therefore an important regulator in iron mobilization pathway at the BBB.There is high demand for iron in the brain, one of the most metabolically active organs in the body (1, 2). Iron is a co-factor of several proteins involved in specialized brain cell functions such as synthesis of neurotransmitters and myelination (3-5). Iron is also necessary for housekeeping functions such as mitochondrial respiration and DNA synthesis, crucial for brain function (5). Insufficient or surplus iron in the brain has been associated with various neurological diseases (6 -10). Although iron deficiency is associated with cognitive and brain structural deficits, excess brain iron is implicated in Alzheimer's, Parkinson's, and other neurodegenerative diseases (10, 11). Therefore, it is not surprising that iron levels are tightly regulated in the brain (10).Iron entry into the brain is regulated by the blood-brain barrier (BBB) 3 (10). This physiological barrier is characterized by tight junctions between brain microvascular endothelial cells (BMVECs) that block passive diffusion of iron into the brain (12). BMVECs are polarized cells with one surface (apical) facing the blood and the other (basal or abluminal) facing interstitial fluid of the brain. BMVECs and ensheathing astrocytes form the regulatory axis of the BBB, modulating iron transport from blood into the brain interstitium (2, 13). It is now known that BMVECs are the focal point for regulation of cerebral iron homeostasis and not mere conduits for iron transport (14). Paracrine fac...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Na+/H+ Exchanger 9 Regulates Iron Mobilization at the Blood-Brain Barrier in Response to Iron Starvation

Beydoun¹,

Hamood²,

Zubieta

et al. 2017

Journal of Biological Chemistry

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“…There were differences between the two WKY strains on behavioral parameters such as lower social interest and lower ultrasonic vocalization calls, suggested that the Charles River strain has traits consistent with ASDs (Zhang-James et al, 2014). We also reported that the SLC9A9 knockout mouse showed ASD-like traits as evidenced by significant decreases in ultrasonic vocalization and increases in repetitive behaviors (Lina Yang, 2016). However the SLC9A9 knockout did not produce other relevant ASD features, such as decreased social behavior (Lina Yang, 2016).…”

Section: : Reviewmentioning

confidence: 95%

“…We also reported that the SLC9A9 knockout mouse showed ASD-like traits as evidenced by significant decreases in ultrasonic vocalization and increases in repetitive behaviors (Lina Yang, 2016). However the SLC9A9 knockout did not produce other relevant ASD features, such as decreased social behavior (Lina Yang, 2016). …”

Section: : Reviewmentioning

confidence: 95%

Endosomal system genetics and autism spectrum disorders: A literature review

Patak

Zhang-James

Faraone

2016

Neuroscience & Biobehavioral Reviews

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Autism spectrum disorders (ASDs) are a group of debilitating neurodevelopmental disorders thought to have genetic etiology, due to their high heritability. The endosomal system has become increasingly implicated in ASD pathophysiology. In an attempt to summarize the association between endosomal system genes and ASDs we performed a systematic review of the literature. We searched PubMed for relevant articles. Simons Foundation Autism Research Initiative (SFARI) gene database was used to exclude articles regarding genes with less than minimal evidence for association with ASDs. Our search retained 55 articles reviewed in two categories: genes that regulate and genes that are regulated by the endosomal system. Our review shows that the endosomal system is a novel pathway implicated in ASDs as well as other neuropsychiatric disorders. It plays a central role in aspects of cellular physiology on which neurons and glial cells are particularly reliant, due to their unique metabolic and functional demands. The system shows potential for biomarkers and pharmacological intervention and thus more research into this pathway is warranted.

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“…A total recording time of 30 min for each rat was divided into six 5-minute segments. 5-Minute segments were chosen based on others and our previous studies to examine locomotor activity and habituation in experimental chambers [51,52]. J Psychiatry Brain Sci.…”

Section: Discussionmentioning

confidence: 99%

Oral Methylphenidate Treatment of an Adolescent ADHD Rat Model Does Not Alter Cocaine-Conditioned Place Preference during Adulthood: A Negative Report

Zhang‐James

Lloyd

James

et al. 2019

J Psychiatry Brain Sci

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The stimulant, methylphenidate (MPH), is commonly used to treat attention deficit hyperactivity disorder (ADHD) and has been increasingly prescribed for school age children and adolescents. Concerns regarding its long-term effects on later substance use disorders (SUDs) have been raised.Previous animal studies have produced contradictory results regarding whether early exposure to MPH increases or protects against SUD in adulthood. The goal of our study was to determine if clinically relevant doses of MPH during adolescence alter cocaine responsiveness in adulthood in a rat model of ADHD, the spontaneous hypertensive rat (SHR).We pretreated SHRs with saline or MPH (2.5 mg/kg once or twice day) via oral gavage during their dark cycle from postnatal day 35 (p35) to p44.Adult rats (p80) were assessed in an eight-session cocaine-conditioned place preference test (CPP). Four doses of cocaine were administered via intraperitoneal injection (i.p.) during the conditioning sessions: 1, 5, 10 and 20 mg/kg. Once per day MPH treatment had a small sensitizing effect on baseline general locomotor activity in a novel environment at p80 as well as a limited suppressive effect on reward-specific locomotor activity as measured by the decreased preference to enter the cocaine-paired chamber. This treatment did not have any effect on the amount of time that rats chose to spend in the cocaine-paired chamber. Twice per day MPH treatment had no effect on locomotion or drug-preference. Our Open Access

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Autism spectrum disorder traits inSlc9a9knock‐out mice

Cited by 20 publications

References 85 publications

Na+/H+ Exchanger 9 Regulates Iron Mobilization at the Blood-Brain Barrier in Response to Iron Starvation

Na+/H+ Exchanger 9 Regulates Iron Mobilization at the Blood-Brain Barrier in Response to Iron Starvation

Endosomal system genetics and autism spectrum disorders: A literature review

Oral Methylphenidate Treatment of an Adolescent ADHD Rat Model Does Not Alter Cocaine-Conditioned Place Preference during Adulthood: A Negative Report

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