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Lysergic Acid Diethylamide (LSD) Promotes Social Behavior Through Mtorc1 in the Excitatory Neurotransmission

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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 Danilo De Gregorioa,b,1, Jelena Popicb,2,3, Justine P. Ennsa,3, Antonio Inserraa,3, Agnieszka Skaleckab, Athanasios Markopoulosa, Luca Posaa, Martha Lopez-Canula, He Qianzia, Christopher K. Laffertyc, Jonathan P. Brittc, Stefano Comaia,d, Argel Aguilar-Vallese, Nahum Sonenbergb,1,4, and Gabriella Gobbia,f,1,4 aNeurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montreal, QC, Canada, H3A 1A1; bDepartment of Biochemistry, McGill University, Montreal, QC, Canada, H3A 1A3; cDepartment of Psychology, McGill University, Montreal, QC, Canada, H3A 1B1; dDivision of Neuroscience, Vita Salute San Raffaele University, 20132 Milan, Italy; eDepartment of Neuroscience, Carleton University, Ottawa, ON, Canada, K1S 5B6; and fMcGill University Health Center, Montreal, QC, Canada, H3A 1A1 Contributed by Nahum Sonenberg, November 10, 2020 (sent for review October 5, 2020; reviewed by Marc G. Caron and Mark Geyer) Clinical studies have reported that the psychedelic lysergic acid receptor (6), but also displays affinity for the 5-HT1A receptor diethylamide (LSD) enhances empathy and social behavior (SB) in (7–9). Several studies have demonstrated that LSD modulates humans, but its mechanism of action remains elusive. Using a glutamatergic neurotransmission and, indirectly, the α-amino- multidisciplinary approach including in vivo electrophysiology, 3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors. optogenetics, behavioral paradigms, and molecular biology, the Indeed, in vitro studies have shown that LSD increased the ex- effects of LSD on SB and glutamatergic neurotransmission in the citatory response of interneurons in the piriform cortex following medial prefrontal cortex (mPFC) were studied in male mice. Acute AMPA (5 μM) application (10). Moreover, the 5-HT2A receptor LSD (30 μg/kg) injection failed to increase SB. However, repeated stimulation produces excitatory postsynaptic potentials (EPSPs) LSD (30 μg/kg, once a day, for 7 days) administration promotes SB, in layer V of the medial PFC (mPFC), thus promoting a release without eliciting antidepressant/anxiolytic-like effects. Optoge- of glutamate in the apical dendritic region of layer V pyramidal netic inhibition of mPFC excitatory neurons dramatically inhibits cells in the mPFC, which in turn activates the AMPA receptors NEUROSCIENCE social interaction and nullifies the prosocial effect of LSD. LSD po- (11). Intriguingly, activation of the AMPA receptor promotes the tentiates the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate N activation of the protein serine/threonine kinase mammalian/ (AMPA) and 5-HT2A, but not -methyl-D-aspartate (NMDA) and 5- mechanistic target of rapamycin complex 1 (mTORC1) signaling, HT1A, synaptic responses in the mPFC and increases the phosphor- which is dysfunctional in several diseases displaying impairment ylation 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 Significance f/f neurons (Raptor :Camk2alpha-Cre), the prosocial effects of LSD and the potentiation of 5-HT2A/AMPA synaptic responses were Social behavior (SB) is a fundamental hallmark of human in- nullified, demonstrating that LSD requires the integrity of mTORC1 teraction. Repeated administration of low doses of the 5-HT2A in excitatory neurons to promote SB. Conversely, in knockout mice agonist lysergic acid diethylamide (LSD) in mice enhances SB by f/f lacking Raptor in GABAergic neurons of the mPFC (Raptor :Gad2- potentiating 5-HT2A and AMPA receptor neurotransmission in Cre), LSD promotes SB. These results indicate that LSD selectively the mPFC via an increasing phosphorylation of the mTORC1, a enhances SB by potentiating mPFC excitatory transmission protein involved in the modulation of SB. Moreover, the inac- through 5-HT2A/AMPA receptors and mTOR signaling. The activa- tivation of mPFC glutamate neurotransmission impairs SB and tion of 5-HT2A/AMPA/mTORC1 in the mPFC by psychedelic drugs nullifies the prosocial effects of LSD. Finally, LSD requires the should be explored for the treatment of mental diseases with SB integrity of mTORC1 in excitatory glutamatergic, but not in impairments such as autism spectrum disorder and social inhibitory neurons, to produce prosocial effects. This study anxiety disorder. unveils a mechanism contributing to the role of 5-HT2A ago- nism in the modulation of SB. LSD | social behavior | mTOR | 5-HT2A | AMPA Author contributions: D.D.G., N.S., and G.G. designed research; D.D.G., J.P., J.P.E., A.I., A.S., A.M., L.P., M.L.-C., H.Q., and G.G. performed research; C.K.L. and J.P.B. contributed ocial behavior (SB) is defined as a set of complex interactions new reagents/analytic tools; D.D.G., J.P., J.P.E., A.I., A.S., A.M., L.P., M.L.-C., H.Q., S.C., and Samong individuals, normally within the same species, that are A.A.-V. analyzed data; and D.D.G., J.P., A.A.-V., N.S., and G.G. wrote the paper. usually beneficial to one individual or group. The prefrontal Reviewers: M.G.C., Duke University Medical Center; and M.G., University of California San cortex (PFC) exerts a pivotal role in the modulation of SB in Diego Medical Center. mammals (1). PFC pathology engenders impaired SB (2) Dis- Competing interest statement: G.G. is a consultant at Diamond Therapeutics Inc, Toronto, ON, Canada. G.G. and D.D.G. are inventors of a provisional patent regarding the use rupted SB is prevalent in various mental illnesses, including of LSD. autism spectrum disorder (ASD) and social anxiety disorders This open access article is distributed under Creative Commons Attribution License 4.0 (SAD) (3), for which few definitive therapies are available. (CC BY). In the past decade, psychedelic drugs have been investigated 1To whom correspondence may be addressed. Email: [email protected], as potential therapeutics in psychiatry. For example, the acute [email protected] or [email protected]. administration of lysergic acid diethylamide (LSD) in humans 2Present address: Department of Neurology and Neurosurgery, McGill University, Mon- produces feelings of happiness, trust, closeness to others, and treal, QC, Canada H3A 2B4. enhanced emotional empathy (4), while promoting positive 3J.P., J.P.E., and A.I. contributed equally to this work. mood changes, altruistic/positive social effects, and well-being/ 4N.S. and G.G. contributed equally to this work. life satisfaction (5). Despite these positive results, the mecha- This article contains supporting information online at https://www.pnas.org/lookup/suppl/ nism of action underlying the prosocial effects of LSD remains doi:10.1073/pnas.2020705118/-/DCSupplemental. elusive. LSD is a partial agonist of the serotonin 5-HT2A Published January 25, 2021. PNAS 2021 Vol. 118 No. 5 e2020705118 https://doi.org/10.1073/pnas.2020705118 | 1of9 Downloaded by guest on September 27, 2021 in SB (12). Moreover, recent evidence showed that the sensiti- S5D), the sociability (SI Appendix, Fig. S5E), or the social novelty zation of the 5-HT2A receptor requires the recruitment of the phase (SI Appendix, Fig. S5F). No effect of LSD was detected on mTORC1 pathway (13). In addition, an in vitro study showed the time spent in each chamber during both social preference that LSD and other psychedelics increase spine density in cor- and social novelty phases (SI Appendix, Fig. S5 A and B). The tical neurons, an effect reverted by the mTORC1 inhibitor effects on locomotion were further investigated in the open field rapamycin (14). However, the role of 5-HT2A and AMPA re- test (OFT) and we found no changes in the distance traveled (SI ceptors as well as that of mTORC1 in orchestrating the behav- Appendix, Fig. S6A) and no difference in the time spent in the ioral effects of LSD in SB has not yet been investigated. Here, we center (SI Appendix, Figs. S6 B and D) or number of entries in dissected the neurobiological mechanisms underlying the pro- the center (SI Appendix, Fig. S6 C and D) of the arena, further social effects of LSD in mice. Employing a multidisciplinary confirming the lack of anxiolytic properties of LSD at our chosen approach, we found that repeated, but not acute, administration dose. During the OFT, we also assessed stereotypic behavior. No of LSD promotes SB by activating cortical AMPA and 5-HT2A differences were detected in the duration and in the number of responses, and that these effects require the integrity of excit- grooming episodes (SI Appendix, Fig. S6 E and F), nor in the atory transmission in the mPFC and an intact mTORC1 complex duration (SI Appendix, Fig. S6G) and the number of rearing in excitatory, but not inhibitory neurotransmission. episodes (SI Appendix, Fig. S6H) between mice treated with LSD or Veh. These results demonstrate that LSD, at this regimen, Results selectively increases social interaction and preference for social Repeated LSD Treatment Increases Social Interaction in the Direct novelty without affecting locomotion and stereotypic behavior or Social Interaction Test (DSI) and the Three Chambers Test (TCT). We anxiety- and depressive-like behaviors. first investigated whether a single (30 μg/kg, i.p.) or repeated (30 μg/kg/day, i.p., for 7 d) LSD administration has an effect on SB. Repeated LSD Treatment Enhances Microiontophoretic Responses of Mice treated with repeated (Fig. 1 A and B) but not a single (SI 5-HT2A and AMPA, but Not 5-HT1A and N-Methyl-D-Aspartate (NMDA) Appendix, Fig. S1) dose of LSD spent more time interacting with Receptors on mPFC Pyramidal Neurons. Next, we investigated which a stranger mouse in the direct social interaction test (DSI), receptors mediate the prosocial effects of LSD within the mPFC. compared with mice treated with vehicle (Veh). We were also Brain imaging studies in humans have shown that the effects of interested to see if this repeated regimen had an effect on de- LSD on SB are mediated by mPFC 5-HT2A receptors (16, 17), spair, anhedonia, anxiety, and stereotypic behavior.
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