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Editor | xi Depression is the most common neuropsychiatric disease in the United States and even in the world.
It severely interferes with patients' senses, thinking and daily activities
.
The search for and development of effective antidepressant compounds has never stopped
.
In recent years, a number of clinical studies have shown that Psilocybin (one of serotonergic psychedelics) can quickly and lastingly relieve the depressive symptoms of patients [1,2]
.
In 2019, the FDA designated psilocybin as "Breakthrough Therapy" and launched a multi-site clinical trial to accelerate the research of psilocybin as a treatment for major depression
.
However, the antidepressant mechanism of psilocybin remains to be elucidated
.
Neuronal structural plasticity plays an important role in the antidepressant effect.
Studies have shown that synaptic atrophy is often accompanied in the brain of depressed patients and animal models, and antidepressant compounds such as ketamine can promote structural plasticity and effectively reverse synaptic deficits [3, 4]
.
Although existing studies have hinted at the relationship between serotonergic psychedelics and neuronal structural and functional plasticity [5,6], it is still unclear how psilocybin regulates neuronal structural or functional plasticity
.
The laboratory of Dr.
Alex Kwan of Yale University School of Medicine has long been engaged in the study of neuron structure and function related to antidepressant compounds
.
In recent years, Dr.
Kwan lab has initiated in vivo research on the antidepressant function of serotonergic psychedelics
.
On July 5, 2021, Alex Kwan's team (postdoctoral fellow Shao Lingxiao is the first author) published an article Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo on Neuron, using long-term in vivo two-photon imaging technology to monitor The dynamic changes of dendritic spines on the same dendrites before and after a single dose of psilocybin, the first time that psilocybin-induced structural plasticity was found, revealing the time scale of synaptic rewiring
.
This study provides important in vivo data support for revealing the rapid and long-lasting antidepressant mechanism of psilocybin
.
First, the researchers confirmed the effective dose of psilocybin in mice through the classic Head-twitch response of serotonergic psychedelics in rodents
.
Subsequently, the learned helplessness paradigm was used to test whether the dose had an effective antidepressant-like behavior.
Here, the researchers used the classic rapid antidepressant compound—ketamine as a positive control
.
Behavioral test results show that 1 mg/kg psilocybin can effectively improve the maladaptive behavior of mice caused by uncontrollable stress
.
Psilocybin is rapidly dephosphorylated into psilocin in the body
.
Psilocin is an agonist of the 5-HT2A receptor
.
Studies have shown that 5-HT2A receptors are highly concentrated on the apical dendrites of layer 5 pyramidal neurons in the medial frontal cortex
.
Therefore, it is suggested that psilocybin may have an effect on the dendritic structure of this type of neuron
.
Therefore, the dynamic changes of the apical dendritic spines of layer 5 pyramidal neurons in the cingulate/premotor (Cg1/M2) area of the medial frontal cortex were tracked through chronic two-photon imaging
.
In the process of dendritic spine morphology detection from three days before administration to one month after administration, the researchers found that psilocybin can rapidly increase the density of this type of dendritic spine in the Cg1/M2 region of female and male mice within 24 hours.
And this phenomenon has been maintained for more than a month
.
Interestingly, it was also found that female mice seem to be more sensitive to psilocybin than male mice
.
As we know, dendritic spines are in a dynamic state under physiological conditions, and the increased dendritic spines density may be mediated by the formation of more new dendritic spines or the elimination of fewer existing dendritic spines
.
For this reason, the researchers compared the dendritic spines formation rate and elimination rate before and after psilocybin administration
.
Experimental results showed that the rate of dendritic spine formation increased the highest in the short term after a single dose of psilocybin, and then decreased in the following days to return to the baseline level and balance with the elimination rate
.
In addition, psilocybin had no significant effect on the elimination rate of dendritic spines
.
This study proved that the long-term increase in dendritic spine density induced by psilocybin was caused by more dendritic spine production at the initial stage of administration
.
However, even under physiological conditions, most of the newly formed dendritic spines are not stable and disappear within a few days, while the surviving dendritic spines will mature and transform into functional synapses within a few days [7]
.
Therefore, the researchers monitored the newborn dendritic spines induced by the administration of psilocybin for 24 hours, and the results showed that ~50% and ~34% of the dendritic spines remained stable on the 7th and 34th days after the administration, respectively.
This value is similar to the control group
.
In summary, the study shows that a single dose of psilocybin can rapidly and lastingly induce dendritic remodeling in the fifth layer of pyramidal neurons in the mouse medial frontal cortex.
At the same time, the newly formed dendritic spines induced by psilocybin can transform.
Into a functional synapse
.
Next, the researchers focused on the molecular target of psilocybin inducing synaptic remodeling
.
Multiple evidences indicate that 5-HT2A receptors are necessary mediators for the psychotomimetic effects of serotonergic psychedelics in humans and the head-twitch response in mice
.
In order to investigate whether the effect of psilocybin on structural plasticity may also be mediated by 5-HT2A receptors, the researchers pretreated the 5-HT2A receptor antagonist ketanserin to inhibit the function of 5-HT2A receptors in the mouse brain
.
The results show that ketanserin can effectively block the head-twitch response of mice, but cannot effectively inhibit the structural plasticity induced by psilocybin
.
In addition, the researchers further explored whether psilocybin has an effect on functional plasticity while inducing structural plasticity
.
Electrophysiological studies have shown that a single dose of psilocybin can enhance excitatory neurotransmission while inducing structural remodeling
.
To further prove the structural plasticity induced by psilocybin, the researchers analyzed the dendritic spine density and morphology of different types of dendrites in multiple brain regions
.
The results of this study corroborate the two-photon imaging experiment and at the same time prove the dependence of psilocybin-induced structural remodeling on brain regions and dendritic types
.
This study proves that for the first time in vivo evidence is provided that psilocybin induces synaptic remodeling, and this process is rapid and long-lasting, suggesting that synaptic rewiring may be a mechanism shared by compounds with rapid antidepressant effects
.
Original link: https://doi.
org/10.
1016/j.
neuron.
2021.
06.
008 Platemaker: 11 References 1.
Davis, AK, Barrett, FS, May, DG, Cosimano, MP, Sepeda, ND, Johnson , MW, Finan, PH, and Griffiths, RR (2020).
Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial.
JAMA Psychiatry.
2.
Carhart-Harris, RL, Bolstridge, M.
, Rucker, J .
, Day, CMJ, Erritzoe, D.
, Kaelen, M.
, Bloomfield, M.
, Rickard, JA, Forbes, B.
, Feilding, A.
, et al.
(2016).
Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study.
The Lancet Psychiatry 3, 619-627.
3.
Duman, RS, and Aghajanian, GK (2012).
Synaptic dysfunction in depression: potential therapeutic targets.
Science 338, 68-72.
4.
Moda-Sava, RN, Murdock, MH, Parekh, PK, Fetcho, RN, Huang, BS, Huynh, TN, Witztum, J.
, Shaver, DC,Rosenthal, DL, Alway, EJ, et al.
(2019).
Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation.
Science 364.
5.
Ly, C.
, Greb, AC, Cameron, LP, Wong, JM, Barragan, EV, Wilson, PC, Burbach, KF, Soltanzadeh Zarandi, S.
, Sood, A.
, Paddy, MR, et al.
(2018).
Psychedelics Promote Structural and Functional Neural Plasticity.
Cell Rep 23, 3170-3182.
6.
Holmes, SE, Scheinost, D.
, Finnema, SJ, Naganawa, M.
, Davis, MT, DellaGioia, N.
, Nabulsi, N.
, Matuskey, D.
, Angarita, GA, Pietrzak, RH, et al.
(2019).
Lower synaptic density is associated with depression severity and network alterations.
Nat Commun 10, 1529.
7.
Knott, GW, Holtmaat, A.
, Wilbrecht, L.
, Welker, E.
, and Svoboda, K.
(2006).
Spine growth precedes synapse formation in the adult neocortex in vivo.
Nat Neurosci 9, 1117-1124.
Reprinting instructions [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author owns all legal rights.
Offenders must be investigated. .
It severely interferes with patients' senses, thinking and daily activities
.
The search for and development of effective antidepressant compounds has never stopped
.
In recent years, a number of clinical studies have shown that Psilocybin (one of serotonergic psychedelics) can quickly and lastingly relieve the depressive symptoms of patients [1,2]
.
In 2019, the FDA designated psilocybin as "Breakthrough Therapy" and launched a multi-site clinical trial to accelerate the research of psilocybin as a treatment for major depression
.
However, the antidepressant mechanism of psilocybin remains to be elucidated
.
Neuronal structural plasticity plays an important role in the antidepressant effect.
Studies have shown that synaptic atrophy is often accompanied in the brain of depressed patients and animal models, and antidepressant compounds such as ketamine can promote structural plasticity and effectively reverse synaptic deficits [3, 4]
.
Although existing studies have hinted at the relationship between serotonergic psychedelics and neuronal structural and functional plasticity [5,6], it is still unclear how psilocybin regulates neuronal structural or functional plasticity
.
The laboratory of Dr.
Alex Kwan of Yale University School of Medicine has long been engaged in the study of neuron structure and function related to antidepressant compounds
.
In recent years, Dr.
Kwan lab has initiated in vivo research on the antidepressant function of serotonergic psychedelics
.
On July 5, 2021, Alex Kwan's team (postdoctoral fellow Shao Lingxiao is the first author) published an article Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo on Neuron, using long-term in vivo two-photon imaging technology to monitor The dynamic changes of dendritic spines on the same dendrites before and after a single dose of psilocybin, the first time that psilocybin-induced structural plasticity was found, revealing the time scale of synaptic rewiring
.
This study provides important in vivo data support for revealing the rapid and long-lasting antidepressant mechanism of psilocybin
.
First, the researchers confirmed the effective dose of psilocybin in mice through the classic Head-twitch response of serotonergic psychedelics in rodents
.
Subsequently, the learned helplessness paradigm was used to test whether the dose had an effective antidepressant-like behavior.
Here, the researchers used the classic rapid antidepressant compound—ketamine as a positive control
.
Behavioral test results show that 1 mg/kg psilocybin can effectively improve the maladaptive behavior of mice caused by uncontrollable stress
.
Psilocybin is rapidly dephosphorylated into psilocin in the body
.
Psilocin is an agonist of the 5-HT2A receptor
.
Studies have shown that 5-HT2A receptors are highly concentrated on the apical dendrites of layer 5 pyramidal neurons in the medial frontal cortex
.
Therefore, it is suggested that psilocybin may have an effect on the dendritic structure of this type of neuron
.
Therefore, the dynamic changes of the apical dendritic spines of layer 5 pyramidal neurons in the cingulate/premotor (Cg1/M2) area of the medial frontal cortex were tracked through chronic two-photon imaging
.
In the process of dendritic spine morphology detection from three days before administration to one month after administration, the researchers found that psilocybin can rapidly increase the density of this type of dendritic spine in the Cg1/M2 region of female and male mice within 24 hours.
And this phenomenon has been maintained for more than a month
.
Interestingly, it was also found that female mice seem to be more sensitive to psilocybin than male mice
.
As we know, dendritic spines are in a dynamic state under physiological conditions, and the increased dendritic spines density may be mediated by the formation of more new dendritic spines or the elimination of fewer existing dendritic spines
.
For this reason, the researchers compared the dendritic spines formation rate and elimination rate before and after psilocybin administration
.
Experimental results showed that the rate of dendritic spine formation increased the highest in the short term after a single dose of psilocybin, and then decreased in the following days to return to the baseline level and balance with the elimination rate
.
In addition, psilocybin had no significant effect on the elimination rate of dendritic spines
.
This study proved that the long-term increase in dendritic spine density induced by psilocybin was caused by more dendritic spine production at the initial stage of administration
.
However, even under physiological conditions, most of the newly formed dendritic spines are not stable and disappear within a few days, while the surviving dendritic spines will mature and transform into functional synapses within a few days [7]
.
Therefore, the researchers monitored the newborn dendritic spines induced by the administration of psilocybin for 24 hours, and the results showed that ~50% and ~34% of the dendritic spines remained stable on the 7th and 34th days after the administration, respectively.
This value is similar to the control group
.
In summary, the study shows that a single dose of psilocybin can rapidly and lastingly induce dendritic remodeling in the fifth layer of pyramidal neurons in the mouse medial frontal cortex.
At the same time, the newly formed dendritic spines induced by psilocybin can transform.
Into a functional synapse
.
Next, the researchers focused on the molecular target of psilocybin inducing synaptic remodeling
.
Multiple evidences indicate that 5-HT2A receptors are necessary mediators for the psychotomimetic effects of serotonergic psychedelics in humans and the head-twitch response in mice
.
In order to investigate whether the effect of psilocybin on structural plasticity may also be mediated by 5-HT2A receptors, the researchers pretreated the 5-HT2A receptor antagonist ketanserin to inhibit the function of 5-HT2A receptors in the mouse brain
.
The results show that ketanserin can effectively block the head-twitch response of mice, but cannot effectively inhibit the structural plasticity induced by psilocybin
.
In addition, the researchers further explored whether psilocybin has an effect on functional plasticity while inducing structural plasticity
.
Electrophysiological studies have shown that a single dose of psilocybin can enhance excitatory neurotransmission while inducing structural remodeling
.
To further prove the structural plasticity induced by psilocybin, the researchers analyzed the dendritic spine density and morphology of different types of dendrites in multiple brain regions
.
The results of this study corroborate the two-photon imaging experiment and at the same time prove the dependence of psilocybin-induced structural remodeling on brain regions and dendritic types
.
This study proves that for the first time in vivo evidence is provided that psilocybin induces synaptic remodeling, and this process is rapid and long-lasting, suggesting that synaptic rewiring may be a mechanism shared by compounds with rapid antidepressant effects
.
Original link: https://doi.
org/10.
1016/j.
neuron.
2021.
06.
008 Platemaker: 11 References 1.
Davis, AK, Barrett, FS, May, DG, Cosimano, MP, Sepeda, ND, Johnson , MW, Finan, PH, and Griffiths, RR (2020).
Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial.
JAMA Psychiatry.
2.
Carhart-Harris, RL, Bolstridge, M.
, Rucker, J .
, Day, CMJ, Erritzoe, D.
, Kaelen, M.
, Bloomfield, M.
, Rickard, JA, Forbes, B.
, Feilding, A.
, et al.
(2016).
Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study.
The Lancet Psychiatry 3, 619-627.
3.
Duman, RS, and Aghajanian, GK (2012).
Synaptic dysfunction in depression: potential therapeutic targets.
Science 338, 68-72.
4.
Moda-Sava, RN, Murdock, MH, Parekh, PK, Fetcho, RN, Huang, BS, Huynh, TN, Witztum, J.
, Shaver, DC,Rosenthal, DL, Alway, EJ, et al.
(2019).
Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation.
Science 364.
5.
Ly, C.
, Greb, AC, Cameron, LP, Wong, JM, Barragan, EV, Wilson, PC, Burbach, KF, Soltanzadeh Zarandi, S.
, Sood, A.
, Paddy, MR, et al.
(2018).
Psychedelics Promote Structural and Functional Neural Plasticity.
Cell Rep 23, 3170-3182.
6.
Holmes, SE, Scheinost, D.
, Finnema, SJ, Naganawa, M.
, Davis, MT, DellaGioia, N.
, Nabulsi, N.
, Matuskey, D.
, Angarita, GA, Pietrzak, RH, et al.
(2019).
Lower synaptic density is associated with depression severity and network alterations.
Nat Commun 10, 1529.
7.
Knott, GW, Holtmaat, A.
, Wilbrecht, L.
, Welker, E.
, and Svoboda, K.
(2006).
Spine growth precedes synapse formation in the adult neocortex in vivo.
Nat Neurosci 9, 1117-1124.
Reprinting instructions [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author owns all legal rights.
Offenders must be investigated. .
