Lysergic acid diethylamide (LSD) promotes social behavior through mTORC1 in the excitatory neurotransmission.
Lysergic acid diethylamide (LSD) promotes social behavior through mTORC1 in the excitatory neurotransmission.
复制标题
DOI：
10.1073/pnas.2020705118
复制
发表时间：
2021-02-02
影响因子：
11.1
通讯作者：
Gobbi G
中科院分区：
文献类型：
--
作者：
De Gregorio D;Popic J;Enns JP;Inserra A;Skalecka A;Markopoulos A;Posa L;Lopez-Canul M;Qianzi H;Lafferty CK;Britt JP;Comai S;Aguilar-Valles A;Sonenberg N;Gobbi G
社会行为（SB）是人类互动的基本标志。重复给药低剂量的5-HT 2A激动剂麦角酰二乙胺（LSD）在小鼠中增强SB通过增强5-HT 2A和AMPA受体的神经传递在mPFC通过增加磷酸化的mTORC 1，一种蛋白质参与SB的调制。此外，失活的mPFC谷氨酸神经传递损害SB和无效的LSD的亲社会的影响。最后，LSD需要mTORC 1在兴奋性神经元中的完整性，而不是在抑制性神经元中，以产生亲社会效应。本研究揭示了5-HT 2A激动剂在SB调节中的作用机制。临床研究报道，迷幻剂麦角酸二乙胺（LSD）增强人类的共情和社会行为（SB），但其作用机制仍然难以捉摸。使用多学科的方法，包括在体内电生理学，光遗传学，行为范例，和分子生物学，LSD对SB和海马能神经传递在内侧前额叶皮层（mPFC）的影响进行了研究在雄性小鼠。急性注射LSD（30 μg/kg）未能增加SB。然而，重复注射LSD（30 μg/kg，每日一次，共7天）可促进SB，而不引起抗抑郁/抗焦虑样作用。mPFC兴奋性神经元的光遗传抑制显著抑制了社会互动，并使LSD的亲社会效应无效。LSD可增强mPFC中α-氨基-3-羟基-5-甲基-4-异恶唑丙酸酯（AMPA）和5-HT 2A的突触反应，但不增强N-甲基-D-天冬氨酸（NMDA）和5-HT 1A的突触反应，并增加丝氨酸-苏氨酸蛋白激酶Akt和mTOR的磷酸化。在缺乏Raptor（mTORC 1复合物的结构成分之一）的条件性敲除小鼠的兴奋性多巴胺能神经元（Raptorf/f：Camk 2alpha-Cre），LSD的亲社会效应和增强5-HT 2A/AMPA突触反应被抵消，表明LSD需要的mTORC 1的完整性在兴奋性神经元，以促进SB。相反，在敲除小鼠缺乏Raptor的GABA能神经元的mPFC（Raptorf/f：Gad 2-Cre），LSD促进SB。这些结果表明，LSD选择性增强SB通过增强mPFC兴奋性传递通过5-HT 2A/AMPA受体和mTOR信号。迷幻药对mPFC中5-HT 2A/AMPA/mTORC 1的激活应被探索用于治疗具有SB损伤的精神疾病，如自闭症谱系障碍和社交焦虑障碍。
Social behavior (SB) is a fundamental hallmark of human interaction. Repeated administration of low doses of the 5-HT2A agonist lysergic acid diethylamide (LSD) in mice enhances SB by potentiating 5-HT2A and AMPA receptor neurotransmission in the mPFC via an increasing phosphorylation of the mTORC1, a protein involved in the modulation of SB. Moreover, the inactivation of mPFC glutamate neurotransmission impairs SB and nullifies the prosocial effects of LSD. Finally, LSD requires the integrity of mTORC1 in excitatory glutamatergic, but not in inhibitory neurons, to produce prosocial effects. This study unveils a mechanism contributing to the role of 5-HT2A agonism in the modulation of SB. Clinical studies have reported that the psychedelic lysergic acid diethylamide (LSD) enhances empathy and social behavior (SB) in humans, but its mechanism of action remains elusive. Using a multidisciplinary approach including in vivo electrophysiology, optogenetics, behavioral paradigms, and molecular biology, the effects of LSD on SB and glutamatergic neurotransmission in the medial prefrontal cortex (mPFC) were studied in male mice. Acute LSD (30 μg/kg) injection failed to increase SB. However, repeated LSD (30 μg/kg, once a day, for 7 days) administration promotes SB, without eliciting antidepressant/anxiolytic-like effects. Optogenetic inhibition of mPFC excitatory neurons dramatically inhibits social interaction and nullifies the prosocial effect of LSD. LSD potentiates the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and 5-HT2A, but not N-methyl-D-aspartate (NMDA) and 5-HT1A, synaptic responses in the mPFC and increases the phosphorylation of the serine-threonine protein kinases Akt and mTOR. In conditional knockout mice lacking Raptor (one of the structural components of the mTORC1 complex) in excitatory glutamatergic neurons (Raptorf/f:Camk2alpha-Cre), the prosocial effects of LSD and the potentiation of 5-HT2A/AMPA synaptic responses were nullified, demonstrating that LSD requires the integrity of mTORC1 in excitatory neurons to promote SB. Conversely, in knockout mice lacking Raptor in GABAergic neurons of the mPFC (Raptorf/f:Gad2-Cre), LSD promotes SB. These results indicate that LSD selectively enhances SB by potentiating mPFC excitatory transmission through 5-HT2A/AMPA receptors and mTOR signaling. The activation of 5-HT2A/AMPA/mTORC1 in the mPFC by psychedelic drugs should be explored for the treatment of mental diseases with SB impairments such as autism spectrum disorder and social anxiety disorder.
登录
查看更多内容
影响因子：
8.8
作者：
Ly C;Greb AC;Cameron LP;Wong JM;Barragan EV;Wilson PC;Burbach KF;Soltanzadeh Zarandi S;Sood A;Paddy MR;Duim WC;Dennis MY;McAllister AK;Ori-McKenney KM;Gray JA;Olson DE
通讯作者：
Olson DE
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1126/science.1190287
发表时间：
2010-08-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Li N;Lee B;Liu RJ;Banasr M;Dwyer JM;Iwata M;Li XY;Aghajanian G;Duman RS
通讯作者：
Duman RS
影响因子：
7.6
作者：
Bambico, Francis Rodriguez;Cassano, Tommaso;Gobbi, Gabriella
通讯作者：
Gobbi, Gabriella
影响因子：
3.4
作者：
Gobbi, G;Janiri, L
通讯作者：
Janiri, L