Correcting miR92a-vGAT-Mediated GABAergic Dysfunctions Rescues Human Tau-Induced Anxiety in Mice

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 g-aminobutyric acid (GABA) level with inhibition of g 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 0 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.

MicroRNA–mediated downregulation of potassium-chloride-cotransporter and vesicular γ-aminobutyric acid transporter expression in spinal cord contributes to neonatal cystitis–induced visceral pain in rats

“…Although previous studies have shown the involvement of miR-92 in post-transcriptional regulation of GABAergic transmission in cerebellar granule neurons and hippocampal memory formation in mice, to our knowledge this is the first report indicating spinal miR-92b-3p in transcriptional dysregulation of GABAergic transmission and development of visceral hyperalgesia in zymosan-induced cystitis [2; 38]. In a recent study, miR-92a-mediated down-regulation of VGAT expression in the hippocampus CA3 region has been implicated as the molecular mechanism of underlying anxiety in patients with Alzheimer’s disease [15]. Although both miR-92a and miR-92b-3p carry identical complementary binding sites for VGAT 3’UTR transcript, however, miR-92a expression was comparable between zymosan and saline-treated rats in the present study.…”

Mitochondrial MicroRNAs in Aging and Neurodegenerative Diseases

“…Li et al (2017) discovered that miR92a plays an important role in tau-related inducement of anxiety in AD [ 23 ]. Tau accumulation in the brain selectively suppresses the expression of the intra-vesicular gamma-aminobutyric acid (GABA) transporter (vGAT) by increasing levels of miR92a, which binds to the vGAT mRNA 3′UTR and inhibits translation.…”

“…Tau accumulation in the brain selectively suppresses the expression of the intra-vesicular gamma-aminobutyric acid (GABA) transporter (vGAT) by increasing levels of miR92a, which binds to the vGAT mRNA 3′UTR and inhibits translation. Intervention at any step of the pathway (injection of a GABA antagonist, upregulating vGAT synthesis, or injection of a miR92a inhibitor) showed attenuation of the mice’s anxiety [ 23 ].…”

Nature of Tau-Associated Neurodegeneration and the Molecular Mechanisms

“…Further studies demonstrated that tau accumulation selectively suppresses expression of the intracellular vesicular GABA transporter (vGAT), among the factors responsible for GABA synthesis, release, uptake, and transport. The mechanism involves an increased miR92a, which targets vGAT mRNA 3’ UTR and inhibits vGAT translation [ 28 ]. These data suggest that the AD-like tau accumulation induces anxiety by disrupting miR92a-vGAT-GABA signaling.…”

“…We found that tau accumulation induces GABA deficits, while upregulating GABA by intraperitoneal injection of midazolam, ChR2-mediated photostimulating and overexpressing vGAT, or blocking miR92a by specific antagomir or inhibitor efficiently rescues tau-induced GABAergic dysfunctions with attenuation of anxiety. These findings may lead to the development of new therapeutics for tauopathies [ 28 ]. We also observed that tau accumulation inhibits nAChRs [ 29 ] and selective dopamine receptor 4 activation mediates the hippocampal neuronal calcium response via IP3 and ryanodine receptors [ 73 ], therefore, preservation or restoration of cholinergic or regulating dopaminergic functions should be beneficial to tau pathologies.…”