P.1.025 Molecular imaging of beta-2 subunit containing nicotinic acetylcholine receptors in major depressive disorder

Abstract Dynamic and reversible RNA methylation has emerged as a new layer of epigenetic regulation of behaviors such as learning and memory; however, whether RNA methylation plays a critical role in the pathophysiology of depression is unclear. Here, we report that expression of the fat mass and obesity associated gene (FTO), a primary RNA demethylase, is downregulated in the hippocampi of both major depressive disorder (MDD) patients and mouse models of depression. Suppressing Fto expression in the hippocampus induces depression-like behaviors in mice, while elevating its expression leads to antidepressant effects. Epitranscriptomic profiling of N6-methyladenosine (m6A) RNA methylation in the hippocampi of Fto knockdown (KD), Fto knockout (cKO), and Fto-overexpressing (OE) mice identified adrenoceptor beta 2 (Adrb2) mRNA as a target of Fto. Adrb2 stimulation reverses the depression-like behaviors and spine loss induced by hippocampal Fto deficiency, possibly via the modulation of hippocampal Sirt1 expression by c-Myc. These findings reveal that Fto in the hippocampus mediates depression-like behaviors and highlight the importance of reversible RNA methylation in driving depression.

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Pharmacological and kinetic properties of alpha 4 beta 2 neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes.

The Journal of Physiology ◽

10.1113/jphysiol.1992.sp019132 ◽

1992 ◽

Vol 450 (1) ◽

pp. 375-394 ◽

Cited By ~ 39

Author(s):

P Charnet ◽

C Labarca ◽

B N Cohen ◽

N Davidson ◽

H A Lester ◽

...

Keyword(s):

Nicotinic Acetylcholine Receptors ◽

Acetylcholine Receptors ◽

Xenopus Oocytes ◽

Kinetic Properties ◽

Neuronal Nicotinic Acetylcholine Receptors ◽

Nicotinic Acetylcholine ◽

Beta 2

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Alpha4beta2 Neuronal Nicotinic Acetylcholine Receptors in the Central Nervous System Are Inhibited by Isoflurane and Propofol, but alpha7-type Nicotinic Acetylcholine Receptors Are Unaffected

Anesthesiology ◽

10.1097/00000542-199704000-00016 ◽

1997 ◽

Vol 86 (4) ◽

pp. 859-865 ◽

Cited By ~ 167

Author(s):

Pamela Flood ◽

Jose Ramirez-Latorre ◽

Lorna Role

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Acetylcholine Receptor ◽

Nicotinic Acetylcholine Receptors ◽

Acetylcholine Receptors ◽

General Anesthetics ◽

Nicotinic Acetylcholine ◽

The Central Nervous System ◽

Beta 2 ◽

Alpha 7

Background The mechanisms of action of general anesthetics are not completely understood. Many general anesthetics are reported to potentiate gamma-aminobutyric acid (GABAA) and glycine receptors in the central nervous system (CNS) and to inhibit the muscle-type nicotinic acetylcholine receptor (nAChR). The effects of general anesthetics on another family of ligand-gated ion channel in the CNS, the nAChRs, have not been defined. Methods Two types of CNS acetylcholine receptor, the alpha 4 beta 2 receptor or the alpha 7 homomeric receptor, were expressed heterologously in Xenopus laevis oocytes. Using the standard two-microelectrode voltage-clamp technique, peak acetylcholinegated current was measured before and after coapplication of isoflurane or propofol. Results Coapplication of either isoflurane or propofol with acetylcholine resulted in potent, dose-dependent inhibition of the alpha 4 beta 2 receptor current with median inhibitory concentrations of 85 and 19 microM, respectively. The inhibition of the alpha 4 beta 2 receptor by both isoflurane and propofol appears to be competitive with respect to acetylcholine. The alpha 7 receptor current was not effected by either anesthetic. Conclusions The CNS-type nAChRs are differentially affected by isoflurane and propofol. The alpha 4 beta 2 receptor is affected by isoflurane more potently than the most sensitive GABAA or glycine receptor that has been reported, whereas the alpha 7 homomeric receptor is not affected by either anesthetic. Inhibition of specific subtypes of nAChRs in the CNS, along with potentiation of GABAA and glycine receptors, may contribute to the effects and side effects of general anesthetics.

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