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The cranial windows of perception

2021; Cell Press; Volume: 109; Issue: 16 Linguagem: Inglês

10.1016/j.neuron.2021.07.017

1097-4199

Jeffrey F. DiBerto, Bryan L. Roth,

Olfactory and Sensory Function Studies

Psilocybin has emerged as a potentially rapidly acting antidepressant with enduring actions. In this issue of Neuron, Shao et al., 2021Shao L.X. Liao C. Gregg I. Davoudian P.A. Savalia N.K. Delagarza K. Kwan A.C. Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo.Neuron. 2021; 109: 2535-2544Abstract Full Text Full Text PDF Scopus (30) Google Scholar show that psilocybin quickly induces dendritic spine formation in cortical layer V pyramidal neurons. These results provide a potential cellular substrate for psilocybin’s therapeutic actions. Psilocybin has emerged as a potentially rapidly acting antidepressant with enduring actions. In this issue of Neuron, Shao et al., 2021Shao L.X. Liao C. Gregg I. Davoudian P.A. Savalia N.K. Delagarza K. Kwan A.C. Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo.Neuron. 2021; 109: 2535-2544Abstract Full Text Full Text PDF Scopus (30) Google Scholar show that psilocybin quickly induces dendritic spine formation in cortical layer V pyramidal neurons. These results provide a potential cellular substrate for psilocybin’s therapeutic actions. If the doors of perception were cleansed, every thing would appear to man as it is, Infinite. For man has closed himself up, till he sees all things thro' narrow chinks of his cavern. −William Blake (The Marriage of Heaven and Hell) Psychedelic drugs such as lysergic acid diethylamide (LSD), psilocybin, mescaline, and N,N’-dimethyltryptamine induce profound alterations in perception and have been used ritualistically by indigenous peoples for millennia (Nichols, 2016Nichols D.E. Psychedelics.Pharmacol. Rev. 2016; 68: 264-355Crossref PubMed Scopus (534) Google Scholar). Although psychedelic drugs were actively studied for their therapeutic potential in the 1950s and 1960s (Nichols, 2016Nichols D.E. Psychedelics.Pharmacol. Rev. 2016; 68: 264-355Crossref PubMed Scopus (534) Google Scholar), widespread recreational use of psychedelics in the 1960s led to their eventual criminalization. Psychedelics are experiencing a renaissance in psychiatry due to several clinical trials demonstrating the potential of one or two doses of psilocybin to cause rapid and enduring improvements in depression and anxiety (Reiff et al., 2020Reiff C.M. Richman E.E. Nemeroff C.B. Carpenter L.L. Widge A.S. Rodriguez C.I. Kalin N.H. McDonald W.M. the Work Group on Biomarkers and Novel Treatments, a Division of the American Psychiatric Association Council of ResearchPsychedelics and Psychedelic-Assisted Psychotherapy.Am. J. Psychiatry. 2020; 177: 391-410Crossref PubMed Scopus (112) Google Scholar). Psilocybin, found in mushrooms of the genus Psilocybe and prodrug of the 5-HT2A receptor (5-HT2AR) agonist psilocin, has gained particular clinical traction after being designated a “breakthrough therapy” for treatment-resistant depression by the United States Food and Drug Administration (hereafter, PSI will interchangeably refer to psilocybin and psilocin). Despite an atomic-level understanding of psychedelic drug actions (Kim et al., 2020Kim K. Che T. Panova O. DiBerto J.F. Lyu J. Krumm B. Wacker D. Robertson M.J. Seven A.B. Nichols David E. et al.Structure of a Hallucinogen-Activated Gq-Coupled 5-HT2A Serotonin Receptor.Cell. 2020; 182: 1574-1588.e1519Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar) and a mushrooming body of literature maintaining psychedelics’ therapeutic potential (Reiff et al., 2020Reiff C.M. Richman E.E. Nemeroff C.B. Carpenter L.L. Widge A.S. Rodriguez C.I. Kalin N.H. McDonald W.M. the Work Group on Biomarkers and Novel Treatments, a Division of the American Psychiatric Association Council of ResearchPsychedelics and Psychedelic-Assisted Psychotherapy.Am. J. Psychiatry. 2020; 177: 391-410Crossref PubMed Scopus (112) Google Scholar), the neurobiological mechanisms by which psychedelic drugs exert their enduring therapeutic effects remain unknown. Many prior studies have demonstrated that antidepressant drugs, including the rapidly acting antidepressant ketamine (Li et al., 2010Li N. Lee B. Liu R.J. Banasr M. Dwyer J.M. Iwata M. Li X.Y. Aghajanian G. Duman R.S. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists.Science. 2010; 329: 959-964Crossref PubMed Scopus (1915) Google Scholar) as well as conventional antidepressants (Benes and Vincent, 1991Benes F.M. Vincent S.L. Changes in dendritic spine morphology in response to increased availability of monoamines in rat medial prefrontal cortex.Synapse. 1991; 9: 235-237Crossref PubMed Scopus (9) Google Scholar), can induce dendritic spine formation. Among many other compensatory alterations in neuronal function induced by antidepressants, spine formation has emerged as a potential final pathway (Moda-Sava et al., 2019Moda-Sava R.N. Murdock M.H. Parekh P.K. Fetcho R.N. Huang B.S. Huynh T.N. Witztum J. Shaver D.C. Rosenthal D.L. Alway E.J. et al.Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation.Science. 2019; 364: eaat8078Crossref PubMed Scopus (230) Google Scholar). Some years ago, Jones et al., 2009Jones K.A. Srivastava D.P. Allen J.A. Strachan R.T. Roth B.L. Penzes P. Rapid modulation of spine morphology by the 5-HT2A serotonin receptor through kalirin-7 signaling.Proc. Natl. Acad. Sci. USA. 2009; 106: 19575-19580Crossref PubMed Scopus (129) Google Scholar reported that the psychedelic drug 2,5-dimethoxy-4-iodoamphetamine rapidly induced spine formation in cortical pyramidal neurons. More recently, others have reported rapid spine formation of cortical neurons in vitro to be a common feature of psychedelic, but not of non-psychedelic, 5-HT2AR agonists (Ly et al., 2018Ly C. Greb A.C. Cameron L.P. Wong J.M. Barragan E.V. Wilson P.C. Burbach K.F. Soltanzadeh Zarandi S. Sood A. Paddy M.R. et al.Psychedelics Promote Structural and Functional Neural Plasticity.Cell Rep. 2018; 23: 3170-3182Abstract Full Text Full Text PDF PubMed Scopus (265) Google Scholar). Collectively these findings have raised the intriguing possibility that psychedelic-drug-induced spine formation and synaptic plasticity might represent one way in which psychedelic drugs exert their therapeutic potential. A key distinguishing feature of the putative therapeutic action of PSI is its enduring action after one dose. In this issue of Neuron, Shao et al., 2021Shao L.X. Liao C. Gregg I. Davoudian P.A. Savalia N.K. Delagarza K. Kwan A.C. Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo.Neuron. 2021; 109: 2535-2544Abstract Full Text Full Text PDF Scopus (30) Google Scholar used two-photon microscopy to show, remarkably, that a single dose of PSI induced sustained alterations in cortical neuron spine formation and plasticity. For these studies, the authors chronically monitored cortical layer V pyramidal neuron apical dendrites, where 5-HT2AR expression is enriched, and quantified spine dynamics as well as the functional consequences of behaviorally relevant doses of PSI on spine structural remodeling in mice (Figure 1). The authors began their study by establishing a behaviorally relevant dose of PSI to use for their experiments. First, they administered mice PSI or saline to determine what doses produce a head-twitch response, a behavioral phenotype in rodents evoked by psychedelics that is characterized by rapid side-to-side head movements. Finding that a 1 mg/kg dose of PSI robustly increases head twitches relative to saline or lower drug doses, the authors next show that this dose also ameliorates escape avoidance behavior in mice subjected to a learned helplessness paradigm. Having established a dose of PSI that produces psychedelic drug-like actions and ameliorates a model stress-coping behavior, the authors next investigated how PSI might alter dendritic spine morphology in vivo. Shao et al. installed cranial windows above the cingulate/premotor cortex of Thy1GFP mice, in which cortical layer V and VI pyramidal neurons were fluorescently labeled. Following a single administration of PSI, the authors quantified thousands of dendritic spines at various time points over the course of about 1 month. They found that PSI modestly, but significantly, increases spine morphological parameters including spine density, head width, and protrusion length. Notably, the formation of new spines occurred rapidly after drug treatment, with the rates of spine protrusion and retraction returning to baseline levels after several days. Of the new spines that form in cingulate/premotor cortex dendrites, about half remained morphologically stable after 1 week, and about one-third remained so after 1 month. Shao et al. next demonstrated that the morphological changes in these regions were correlated with elevated synaptic function. Since cortical layer V neurons receive dense glutamatergic innervation, the authors used whole-cell electrophysiology to record miniature excitatory postsynaptic currents (mEPSCs) in these cells. At 24 h after drug administration, they observed a significant increase in mEPSC frequency and a moderate increase in mEPSC amplitude in neurons from PSI- versus saline-treated mice. Given that many PSI-induced dendrites persist 1 month following treatment, it would be of interest to determine the extent to which this increased excitability is maintained over a longer period of time. Shao et al. also examined infralimbic/prelimbic and motor cortex to determine if PSI’s effects generalize across cortical areas. Using confocal microscopy, they again compared spine characteristics between PSI- versus saline-treated mice 24 h after drug administration. Although the changes they observed in these regions were less pronounced and inconsistent in the morphological parameters effected (e.g., protrusion length), the authors concluded that PSI broadly alters spines in cortical layer V pyramidal neurons. If spine remodeling is related to PSI’s therapeutic effects, the heterogeneity across cortical areas observed in this study could provide clues to the locus or loci for PSI’s potential therapeutic actions. A particularly intriguing finding from this study is that pretreatment of mice with 1 mg/kg ketanserin, a 5-HT2A/CR antagonist, completely blocks PSI-evoked head twitches without significantly affecting spine remodeling in the cingulate/premotor cortex. A recent study by Hesselgrave et al. conducted in rats similarly found that 2 mg/kg ketanserin reduces PSI’s ability to evoke head twitches but not its antidepressant-like behavioral effects in the forced-swim test (Hesselgrave et al., 2021Hesselgrave N. Troppoli T.A. Wulff A.B. Cole A.B. Thompson S.M. Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice.Proc. Natl. Acad. Sci. USA. 2021; 118 (e2022489118)Crossref PubMed Scopus (36) Google Scholar). Shao et al. note, however, that ketanserin has poor brain penetration and that results could be different with more potent and selective 5-HT2AR antagonists. An alternative is that although 5-HT2ARs are necessary for psychedelics’ hallucinogenic and hallucinogenic-like effects in humans and rodents, because PSI and other psychedelics activate many other serotonin receptors (Kim et al., 2020Kim K. Che T. Panova O. DiBerto J.F. Lyu J. Krumm B. Wacker D. Robertson M.J. Seven A.B. Nichols David E. et al.Structure of a Hallucinogen-Activated Gq-Coupled 5-HT2A Serotonin Receptor.Cell. 2020; 182: 1574-1588.e1519Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar, Nichols, 2016Nichols D.E. Psychedelics.Pharmacol. Rev. 2016; 68: 264-355Crossref PubMed Scopus (534) Google Scholar), these “off-target” actions of PSI might be therapeutically important. As suggested by Hesselgrave et al., 2021Hesselgrave N. Troppoli T.A. Wulff A.B. Cole A.B. Thompson S.M. Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice.Proc. Natl. Acad. Sci. USA. 2021; 118 (e2022489118)Crossref PubMed Scopus (36) Google Scholar, PSI and other psychedelics may exert their therapeutic actions by virtue of their robust polypharmacology. This study by Shao et al. is the first to demonstrate an enduring action of a psychedelic drug on spine morphology in vivo. Indeed, a similar phenomenon has been observed in response to another rapid-acting antidepressant, the dissociative drug ketamine (Li et al., 2010Li N. Lee B. Liu R.J. Banasr M. Dwyer J.M. Iwata M. Li X.Y. Aghajanian G. Duman R.S. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists.Science. 2010; 329: 959-964Crossref PubMed Scopus (1915) Google Scholar). These convergent biological consequences to drugs diverging in their pharmacological sites of action merit further investigation, as the signaling pathways responsible for them may elucidate alternative drug targets with more direct action and greater clinical efficacy. While the behavioral consequences of psychedelic spine remodeling were not directly assessed by Shao et al., Moda-Sava et al. used a photoactivable, synapse-targeted Rac1 to optogenetically reverse ketamine-induced spine remodeling, blocking its lasting but not initial antidepressant-like effects (Moda-Sava et al., 2019Moda-Sava R.N. Murdock M.H. Parekh P.K. Fetcho R.N. Huang B.S. Huynh T.N. Witztum J. Shaver D.C. Rosenthal D.L. Alway E.J. et al.Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation.Science. 2019; 364: eaat8078Crossref PubMed Scopus (230) Google Scholar). A similar approach may be useful for future studies to understand the necessity of psychedelic-induced spine remodeling to elicit and maintain a therapeutic response. We thank Gavin P. Schmitz for providing sample electrophysiology tracings. Work was supported in the Roth lab by R37DA04567 . Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivoShao et al.NeuronJuly 5, 2021In BriefPsilocybin is a classical psychedelic that shows promise as a treatment for depression. Shao et al. show that psilocybin administration leads to long-lasting modifications to the neural architecture in mice. The increases in the density and strength of neuronal connections may underlie the enduring behavioral effects of the compound. Full-Text PDF Open Archive