Epigenetic regulation of dorsal raphe GABA B1a  associated with isolation-induced abnormal responses to social stimulation in mice

Araki, Ryoko; Hiraki, Yosuke; Nishida, Shoji; Kuramoto, Nobuyuki; Matsumoto, Kinzo; Yabe, Takeshi

doi:10.1016/j.neuropharm.2015.09.013

Cited by 31 publications

(15 citation statements)

References 66 publications

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“…However, considering the fact that when administration of KST was conducted for almost a same period by the therapeutic procedure, KST did not affect ISO-induced behavioral abnormalities, it is very likely that KST may be able to block processes including epigenetic alteration, which is triggered early after starting ISO. Recent findings reported by Araki et al have demonstrated that ISO induces epigenetic changes in promoter coding regions of the GABA B1a receptor [40] and srd5a1 [41], a gene coding for the biosynthetic enzyme neurosteroid allopregnanolone, which is down-regulated by ISO [16, 42]. Moreover, our preliminary study indicated that inhibition of allopregnanolone biosynthesis in the brain caused impairment of sociability behavior in mice in a manner reversible by systemic administration of allopregnanolone (unpublished data).…”

Section: Discussionmentioning

confidence: 99%

Daily administration of yokukansan and keishito prevents social isolation-induced behavioral abnormalities and down-regulation of phosphorylation of neuroplasticity-related signaling molecules in mice

Fujiwara

Han

Awale

et al. 2017

BMC Complement Altern Med

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BackgroundOur previous studies demonstrated that post-weaning social isolation (ISO) in mice induces behavior abnormalities such as deficits of sociability- and attention-like behaviors. These deficits can be attenuated by methylphenidate (MPH), a drug used for attention deficit hyperactivity disorder (ADHD), suggesting that ISO mice offer a potential animal model of comorbid developmental disorder with ADHD and autism spectrum disorder symptoms. This study investigated the effects of Kampo formulae, yokukansan (YKS) and keishito (KST), on the neuropsychiatric symptoms of ISO mice to clarify the therapeutic or preventive/delaying potential of these formulae for the treatment of neurodevelopmental disorders.MethodsThree-to-4-week old male ICR mice were socially isolated during an experimental period and YKS and KST (1523.6 and 2031.8 mg/kg, p.o.) was administered starting from week 2 and week 0 after starting ISO for the analysis of their therapeutic and preventive/delaying potentials, respectively. Sociability, attention-related behavior and fear memory were elucidated by a 3 chamber test, a water-finding test and fear conditioning test, respectively. Moreover, the phosphorylation of neuroplasticity-related signaling molecules in mice hippocampus was analyzed using western blotting.ResultsIn a therapeutic procedure, YKS ameliorated ISO-induced impairments of attention-like behavior and context-dependent fear memory, but not of sociability, whereas KST had no beneficial effects in ISO mice. In experiments to analyze the preventive/delaying potentials of these treatments, both YKS and KST improved sociability, attention, and context-dependent fear memory deficits. The improvement of sociability in mice by YKS and KST was not inhibited by a dopamine D1 receptor antagonist, suggesting that YKS and KST improved the ISO-induced sociability deficit by other mechanisms besides activation of the dopaminergic system. On the other hand, the beneficial effects of YKS and KST on attention-like behavior were inhibited by a muscarinic antagonist, suggesting that YKS and KST ameliorated ISO-induced attention-like behavior through a cholinergic mechanism. Moreover, the phosphorylated forms of CaMKII and CREB were down-regulated by ISO stress and restored by YKS and KST administration.ConclusionsThese findings suggest that YKS and KST may be useful for the improvement of neurodevelopmental disorders.Electronic supplementary materialThe online version of this article (doi:10.1186/s12906-017-1710-7) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Daily administration of yokukansan and keishito prevents social isolation-induced behavioral abnormalities and down-regulation of phosphorylation of neuroplasticity-related signaling molecules in mice

Fujiwara

Han

Awale

et al. 2017

BMC Complement Altern Med

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“…Animal and human research indicates that experience is associated with differences in mC (20)(21)(22)(23). In an early example, high maternal care in rats (high maternal licking and grooming of pups) was associated with reduced mC at the promoter of the glucocorticoid receptor (GR) gene (Nr3c1) involved in the regulation of the stress response (20,21).…”

Section: Dna Modificationsmentioning

confidence: 99%

Biological embedding of experience: A primer on epigenetics

Aristizabal

Anreiter

Halldorsdottir

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

183

102

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Biological embedding occurs when life experience alters biological processes to affect later life health and well-being. Although extensive correlative data exist supporting the notion that epigenetic mechanisms such as DNA methylation underlie biological embedding, causal data are lacking. We describe specific epigenetic mechanisms and their potential roles in the biological embedding of experience. We also consider the nuanced relationships between the genome, the epigenome, and gene expression. Our ability to connect biological embedding to the epigenetic landscape in its complexity is challenging and complicated by the influence of multiple factors. These include cell type, age, the timing of experience, sex, and DNA sequence. Recent advances in molecular profiling and epigenome editing, combined with the use of comparative animal and human longitudinal studies, should enable this field to transition from correlative to causal analyses.

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“…; Araki et al. ; Li and Kirby ). In addition, the manipulation of 5‐HT 1A autoreceptors in the DR affects 5‐HT neuronal firing, determines the responsiveness to stress in depression‐related tasks and alters behavioral responses to antidepressant drugs in mice (Richardson‐Jones et al.…”

Section: Introductionmentioning

confidence: 99%

“…Recently, emerging evidence has shown that GABA A and GABA B receptor-mediated neurotransmissions of the DR are highly involved in drug-related stress, aggression, social avoidance, abnormal responses to social stimulation, and stress-related psychiatric disorders, such as depression (Takahashi et al 2010(Takahashi et al , 2012Challis et al 2013;Araki et al 2016;Li and Kirby 2016). In addition, the manipulation of 5-HT 1A autoreceptors in the DR affects 5-HT neuronal firing, determines the responsiveness to stress in depressionrelated tasks and alters behavioral responses to antidepressant drugs in mice (Richardson-Jones et al 2010).…”

Section: Introductionmentioning

confidence: 99%

Inactivation of GIRK channels weakens the pre‐ and postsynaptic inhibitory activity in dorsal raphe neurons

Llamosas

Ugedo

Torrecilla

2017

Physiological Reports

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The serotonergic tone of the dorsal raphe (DR) is regulated by 5‐HT 1A receptors, which negatively control serotonergic activity via the activation of G protein‐coupled inwardly rectifying K+ (GIRK) channels. In addition, DR activity is modulated by local GABAergic transmission, which is believed to play a key role in the development of mood‐related disorders. Here, we sought to characterize the role of GIRK2 subunit‐containing channels on the basal electrophysiological properties of DR neurons and to investigate whether the presynaptic and postsynaptic activities of 5‐HT 1A, GABAB, and GABAA receptors are affected by Girk2 gene deletion. Whole‐cell patch‐clamp recordings in brain slices from GIRK2 knockout mice revealed that the GIRK2 subunit contributes to maintenance of the resting membrane potential and to the membrane input resistance of DR neurons. 5‐HT 1A and GABAB receptor‐mediated postsynaptic currents were almost absent in the mutant mice. Spontaneous and evoked GABAA receptor‐mediated transmissions were markedly reduced in GIRK2 KO mice, as the frequency and amplitude of spontaneous IPSCs were reduced, the paired‐pulse ratio was increased and GABA‐induced whole‐cell currents were decreased. Similarly, the pharmacological blockade of GIRK channels with tertiapin‐Q prevented the 5‐HT 1A and GABAB receptor‐mediated postsynaptic currents and increased the paired‐pulse ratio. Finally, deletion of the Girk2 gene also limited the presynaptic inhibition of GABA release exerted by 5‐HT 1A and GABAB receptors. These results indicate that the properties and inhibitory activity of DR neurons are highly regulated by GIRK2 subunit‐containing channels, introducing GIRK channels as potential candidates for studying the pathophysiology and treatment of affective disorders.

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Epigenetic regulation of dorsal raphe GABA B1a associated with isolation-induced abnormal responses to social stimulation in mice

Cited by 31 publications

References 66 publications

Daily administration of yokukansan and keishito prevents social isolation-induced behavioral abnormalities and down-regulation of phosphorylation of neuroplasticity-related signaling molecules in mice

Daily administration of yokukansan and keishito prevents social isolation-induced behavioral abnormalities and down-regulation of phosphorylation of neuroplasticity-related signaling molecules in mice

Biological embedding of experience: A primer on epigenetics

Inactivation of GIRK channels weakens the pre‐ and postsynaptic inhibitory activity in dorsal raphe neurons

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