Psilocybin Triggers Synaptic Remodeling
Post by Shireen Parimoo
What's the science?
Psychedelics are hallucinogenic compounds that alter perception, mood, and cognition. Although they are most commonly known for recreational use, psychedelics are increasingly being recognized for their therapeutic potential to treat psychiatric disorders like major depression and PTSD. Psilocybin, commonly referred to as magic mushrooms, is a serotonergic psychedelic substance that is currently being tested in clinical trials to treat depression. Currently, the efficacy of psilocybin use on depressive symptoms and its impact on neuronal functioning are unclear. This week in Neuron, Shao and colleagues examined the impact of a single dose of psilocybin on learned helplessness behavior in mice, as well as its impact on dendritic structure and functioning of the medial prefrontal cortex (mPFC).
How did they do it?
Six- to ten-week-old mice underwent a learned helplessness protocol in which they were given hundreds of inescapable foot shocks on two consecutive days. On the third day, the mice were tested on their learned helplessness behavior by receiving foot shocks that they could avoid by escaping into a different chamber. The authors measured the time it took the mice to escape (escape latency) and recorded escape failures if the mice failed to leave the chamber within 10 seconds of receiving the foot shocks. They used a statistical clustering technique (k-means clustering) on these measures to classify mice as “susceptible” or “resilient” to learned helplessness. After receiving a single dose of either saline, ketamine, or psilocybin treatment on the fourth day, the mice were once again tested on learned helplessness on the fifth day (Test 2).
To examine the effects of psilocybin on mPFC neurons, 2-photon imaging was performed to characterize dendritic spine properties prior to and after treatment. Specifically, the authors assessed spine width, protrusion length, density, formation rate, and elimination rate up to 34 days after saline and psilocybin treatment. Lastly, they performed whole-cell electrophysiological recordings to determine whether psilocybin modulated the activity of pyramidal neurons in the mPFC.
What did they find?
Psilocybin treatment reduced escape failures at Test 2, including in nearly all the mice that were considered to be particularly susceptible to learned helplessness. A single dose of psilocybin also resulted in morphological changes on dendrites, including an increase in spine width, longer spine protrusions, and greater spine density due to an increase in the formation of new dendritic spines (rather than reduced elimination of spines). In fact, half of the newly formed spines remained intact after a week, and up to 37% of those remained intact after a month. Interestingly, the long-term stability of these new dendritic spines was only seen on some dendrites, which suggests that certain sub-population of neurons in the cingulate/premotor mPFC might be more amenable to the effects of psilocybin than others. The authors further replicated this pattern of results in the primary motor cortex and in the prelimbic/infralimbic regions of the mPFC, showing the generalizability of psilocybin’s effects on dendritic remodeling. Lastly, psilocybin led to increased miniature excitatory potentials 24 hours after administration, as compared to saline treatment. Together, these findings demonstrate that a single dose of psilocybin triggers dendritic remodeling, enhances excitatory neurotransmission in the mPFC, and is sufficient to reduce depressive symptoms like learned helplessness in mice.
What's the impact?
This study shows that a single dose of psilocybin quickly triggers both behavioral and synaptic changes in the mouse mPFC. The therapeutic potential for psilocybin use is particularly exciting because many antidepressants take several weeks to have a noticeable effect on behavior and cognition. This study provides a promising first step in understanding how psilocybin affects different brain regions implicated in major depression and paves the way for future research to extend these findings to humans.
Shao et al. Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo. Neuron (2021). Access the original scientific publication here.