Correcting miR92a-vGAT-Mediated GABAergic Dysfunctions Rescues Human Tau-Induced Anxiety in Mice.
Mol Ther
; 25(1): 140-152, 2017 01 04.
Article
em En
| MEDLINE
| ID: mdl-28129110
ABSTRACT
Patients with Alzheimer's disease (AD) commonly show anxiety behaviors, but the molecular mechanisms are not clear and no efficient intervention exists. Here, we found that overexpression of human wild-type, full-length tau (termed htau) in hippocampus significantly decreased the extracellular γ-aminobutyric acid (GABA) level with inhibition of γ oscillation and the evoked inhibitory postsynaptic potential (eIPSP). With tau accumulation, the mice show age-dependent anxiety behaviors. Among the factors responsible for GABA synthesis, release, uptake, and transport, we found that accumulation of htau selectively suppressed expression of the intracellular vesicular GABA transporter (vGAT). Tau accumulation increased miR92a, which targeted vGAT mRNA 3' UTR and inhibited vGAT translation. Importantly, we found that upregulating GABA tones by intraperitoneal injection of midazolam (a GABA agonist), ChR2-mediated photostimulating and overexpressing vGAT, or blocking miR92a by using specific antagomir or inhibitor efficiently rescued the htau-induced GABAergic dysfunctions with attenuation of anxiety. Finally, we also demonstrated that vGAT level decreased while the miR92a increased in the AD brains. These findings demonstrate that the AD-like tau accumulation induces anxiety through disrupting miR92a-vGAT-GABA signaling, which reveals molecular mechanisms underlying the anxiety behavior in AD patients and potentially leads to the development of new therapeutics for tauopathies.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ansiedade
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Tauopatias
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MicroRNAs
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Proteínas da Membrana Plasmática de Transporte de GABA
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Neurônios GABAérgicos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article