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Deficiency of transmembrane AMPA receptor regulatory protein γ-8 leads to attention-deficit hyperactivity disorder-like behavior in mice.

ABSTRACT: Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder prevalent in school-age children. At present, however, its etiologies and risk factors are unknown. Transmembrane α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor regulatory protein γ-8 (TARP γ-8, also known as calcium voltage-gated channel auxiliary subunit gamma 8 (CACNG8)) is an auxiliary AMPA receptor (AMPAR) subunit. Here, we report an association between TARP γ-8 and ADHD, whereby adolescent TARP γ-8 knockout (KO) mice exhibited ADHD-like behaviors, including hyperactivity, impulsivity, anxiety, impaired cognition, and memory deficits. Human single-nucleotide polymorphism (SNP) analysis also revealed strong associations between intronic alleles in CACNG8 genes and ADHD susceptibility. In addition, synaptosomal proteomic analysis revealed dysfunction of the AMPA glutamate receptor complex in the hippocampi of TARP γ-8 KO mice. Proteomic analysis also revealed dysregulation of dopaminergic and glutamatergic transmissions in the prefrontal cortices of TARP γ-8 KO mice. Methylphenidate (MPH), which is commonly used to treat ADHD, significantly rescued the major behavioral deficits and abnormal synaptosomal proteins in TARP γ-8 KO mice. Notably, MPH significantly reversed the up-regulation of Grik2 and Slc6a3 in the prefrontal cortex. MPH also significantly improved synaptic AMPAR complex function by up-regulating other AMPAR auxiliary proteins in hippocampal synaptosomes. Taken together, our results suggest that TARP γ-8 is involved in the development of ADHD in humans. This study provides a useful alternative animal model with ADHD-like phenotypes related to TARP γ-8 deficiency, which has great potential for the development of new therapies.

SUBMITTER: Bai WJ

PROVIDER: S-EPMC9486526 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Deficiency of transmembrane AMPA receptor regulatory protein γ-8 leads to attention-deficit hyperactivity disorder-like behavior in mice.

Bai Wan-Jun WJ Luo Xing-Guang XG Jin Bao-Hua BH Zhu Kang-Sheng KS Guo Wen-Yan WY Zhu Xiao-Que XQ Qin Xia X Yang Zu-Xiao ZX Zhao Jiao-Jiao JJ Chen Si-Ruan SR Wang Ri R Hao Jie J Wang Fei F Shi Yun Stone YS Kong De-Zhi DZ Zhang Wei W

Zoological research 20220901 5

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder prevalent in school-age children. At present, however, its etiologies and risk factors are unknown. Transmembrane α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor regulatory protein γ-8 (TARP γ-8, also known as calcium voltage-gated channel auxiliary subunit gamma 8 (CACNG8)) is an auxiliary AMPA receptor (AMPAR) subunit. Here, we report an association between TARP γ-8 and ADHD, whereby adolescen ...[more]

PMID: 36031768

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Project description:Background and objectiveMounting evidence showed that lead exposure increased the risk of child attention-deficit-hyperactivity disorder (ADHD). Epidemiologic studies have typically used the blood-lead as a biomarker of lead exposure; blood-lead levels mostly reflect recent lead exposure. However, few studies have examined the relationship between bone-lead, a biomarker of cumulative exposure, and ADHD. Therefore, we aimed to compare the associations of bone-lead vs blood-lead levels with child ADHD symptoms and comorbidities.MethodsA total of 164 children aged 3-15 years were enrolled during 2014-2015. The Vanderbilt-ADHD-Diagnostic-Parent-Rating Scale (VADPRS) was used to evaluate the children's ADHD symptoms and comorbidities. Children's blood and bone lead concentrations were assessed, the latter using a non-invasive K-X-ray-fluorescence technique. According to blood-lead levels, children were classified into high (blood-lead ≥ 10.0 μg/dL) and low (blood-lead < 10.0 μg/dL) blood-lead groups. According to bone-lead levels, children were classified into high (bone-lead ≥ 2.66 μg/g) and low (bone-lead < 2.66 μg/g) bone-lead groups. We associated blood/bone lead with VADPRS data using multi-variable binary logistic regression models.ResultsChildren in the high blood-lead group had higher hyperactivity/impulsivity (P = 0.02) scores than the corresponding low blood-lead group. Children in the high bone-lead group had higher hyperactivity/impulsivity (P = 0.02) and oppositional-defiant-disorder (ODD) (P = 0.03) scores than the corresponding low bone-lead group. After adjusting for relevant confounders, children in the high bone-lead group were more likely to have ODD-behavior than the low group (OR = 6.7, 95%CI: 1.2-36.5). However, no adjusted association was observed between blood-lead and any ADHD-domain score.ConclusionHigh levels of cumulative lead exposure in children may be an independent risk factor of ODD-behavior.

Dataset Information

Deficiency of transmembrane AMPA receptor regulatory protein γ-8 leads to attention-deficit hyperactivity disorder-like behavior in mice.

Publications

Deficiency of transmembrane AMPA receptor regulatory protein γ-8 leads to attention-deficit hyperactivity disorder-like behavior in mice.

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