Neuroscientists have been curious about a link between ketamine and neuroplasticity in treating PTSD and treatment-resistant depression for some time; now they say, they might have discovered some important clues. Researchers based at the Institute of Science and Technology Austria report that ketamine increases neuroplasticity in the brain, but there’s a catch; they only saw this effect in females.
As per a press release, ‘We didn’t expect to see this; it was a surprising finding.,’ said Sandra Siegert, professor at the Institute of Science and Technology Austria and senior author of the study. Siegert and her staff have discovered that female mice recovering from a dose of ketamine undergo physical changes that can help to rewire their brains. In another odd twist, the reprogramming effect that seems to rev up their neuroplasticity is linked to how our brains respond to stress hormones – including cortisol.
Could harnessing the biology underlying this sex-specific return to neuroplasticity help us to develop new therapeutic applications for ketamine?
‘Understanding how to balance good plasticity versus maladaptive plasticity is very important for healthy life, healthy aging, and neuropsychiatric diseases,’ said collaborator Bosiljka Tasic, Director of Molecular Genetics at the Allen Institute and one of the study’s co-authors. ‘How can you modify and modulate this plasticity but in a positive way? Many of the major plasticity-inducing drugs have become quite interesting, especially as treatments for depression, but we still don’t know how they work.’
What is ketamine?
We’ve all heard of ketamine by now, whether as a miracle drug for treatment-resistant depression (unconfirmed), a psychedelic party drug (Succession) or as a veterinary medicine (horse tranquillizer).
Underneath all the hue and cry, ketamine is actually quite an interesting drug in its own right. Unlike most anaesthetics, it works by blocking communication between certain types of neurons, making us feel disconnected from our bodies.
At clinical doses, this helps to prevent us from feeling pain, and can make us go into a dreamlike sedated state. At recreational doses, people experience dissociation and our brains play tricks on us to help us explain the strange disconnect between our minds and bodies.
So what does this have to do with neuroplasticity?
Sex, Drugs and Neuroplasticity
Researchers first noticed that ketamine does some odd things to neuroplasticity in baby animal brains as far back as 1987. Scientists looking into how we learn to see noted that ketamine slowed down or reversed the end of the critical period of neuroplasticity in the visual cortex. This sparked a decades-long race by scientists to find out what ketamine was doing and if these effects could be harnessed and used to treat human brain conditions.
By the 2020s scientists at the Institute of Science and Technology Austria were investigating whether ketamine’s effects on the neuroplasticity of the visual cortex were down to changes in the architecture of the brain. The proteins that coat and stick cells together help the brain to keep its shape and allow neurons to connect. Researchers working for Professor Sandra Siegert were trying to get to grips with the exact mechanism of how and why ketamine was loosening up the tissue around the neurons, permitting them to create new contacts and change paths.
The team had found that giving repeated doses of ketamine to adult mice reorganized the cells in the mice’s brains. The part of those mice’s brain that processes visual input had started to look more like that of a baby mouse, with high levels of neuroplasticity than an adult’s brain.
After a good amount of checking, the brain scientists, led by Alessandro Venturino, PhD, backed Siegert, realized that only female mice experienced the changes. Not only this but in the past, other researchers had noticed that female mice, specifically, were often twitchy and unsettled after waking from a round of ketamine sedation. What was ketamine doing in female brains? Venturino and Siegert set out to find out.
Ketamine Clues
Researchers have understood for a while that, in addition to blocking glutamate N-methyl-d-aspartate receptors (NMDAR), ketamine can trigger changes to immune cells. It turns out that these immune cells, microglia and astrocytes, have a specialized role in helping to protect our brain cells, and when they malfunction, they can contribute to depression. Microglia are a special type of macrophage – the white blood cells that live in our tissue keeping an eye out for dead cells, debris and pathogens that need clearing out.
What’s really surprising is that these cells have another role early on in our neurodevelopment. In young, very neuroplastic brains, scientists often see microglial cells busy at work. In more mature brains, microglia are mostly just hanging out. Researchers have recently shown that astrocytes, activated by the stress hormone cortisol, are in charge of ending critical period neuroplasticity.
So what happens to microglia when they get a shot of ketamine?
Brain Cells Passing in the Night
Venturino did some truly amazing experiments to kick off his investigation. He used in vivo live imaging microscopy to watch in real time what happened in a mouse’s visual cortex when he dosed it with ketamine. The team used special transgenic mice with fluorescent glowing microglial cells and glow in the dark neurons to see whether ketamine increased their numbers, got them moving or made them change shape.
Around an hour after being dosed with ketamine, in female brains, the microglia started changing shape and wiggling around. Venturino recorded them reaching out for the little finger-like structures (dendrites) that neurons used to form synapses with other cells, and establishing new connections. The microglia cuddled up to the excitatory neurons, and the neurons sent out spiny projections to make more points of contact. Once the mice started waking up, the microglia calmed down, but the neurons still had more pokey dendrites than before.
The team also saw this effect in a few male mice, but it was never consistent.
When the team tested to see if these new connections were functional, they were able to detect an increase in electrical signals firing in those neurons. Was this because of the microglia, or was ketamine directly boosting synapses in the neurons? After they killed off the microglia and dosed the mice with ketamine, they saw that neurons didn’t put out more spines. Neither could the researchers detect the spontaneous electrical activity. The scientists concluded that it was the microglia cosying up to the neurons that got them excited, not ketamine, and exclusively in female mice.
Female mice treated with ketamine had the same number of microglia and astrocytes as regular mice, but they had new connections between microglia and neurons, and the neurons had more projections.
Separating Microglia and Neurons
The team collected brain cells from mice treated with ketamine and a set of control mice treated with saline solution. They sorted the cells and used special next generation sequencing equipment to identify every gene that was switched on in each cell. Overall they found that not much changed. They looked for the 2000 genes with the biggest differences between ketamine treated mice and saline treated mice and the biggest differences between the genes turned on in astrocytes/microglia, relative to the ones activated in neurons.
The next step was to find out whether ketamine was changing the genes expressed by brain cells. What was different about female brains? What was ketamine doing?
Ketamine and Stress Hormones
Not much changed in the neurons, but the researchers saw some very interesting differences when they looked at the astrocytes and microglia. Lots of genes that are connected to glucocorticoids, hormones involved in stress, metabolism and the immune system were elevated. One gene in particular stopped them in their tracks. The gene Fkbp5, a stress modulator.
Venturino put all his chips on Fkbp5, launching an investigation into the gene and what it was doing. He found that Fkbp5 was expressed at significantly higher levels in the microglia of female mice treated with ketamine. The team didn’t see this change in neurons, just microglia. Males didn’t show any change in their Fkbp5, with or without ketamine.
The next step was to figure out what the gene was doing. One of the effects of glucocorticoid signalling is to activate macrophages. The team discovered that blocking or deleting the Fkbp5 prevented ketamine from activating microglia. What’s more, when they tested for those excitatory signals they saw before when the microglia got up close and personal with the neurons, the mice with no Fkbp5 didn’t have them. So ketamine needs the Fkbp5 gene to trigger the microglia to form new connections with neurons.
A Sex-Specific Process
The final step was to see whether the stress hormone cortisol was involved in activating the microglia in response to ketamine. They stopped the mice from making cortisol by removing their adrenal glands. Removing the mice’s adrenal glands didn’t affect a regular mouse’s microglia or neurons, or how they interacted with each other. When it came to ketamine’s effect on microglia, however, things were different. Removing the female mice’s adrenal glands blocked ketamine’s ability to trigger new microglia/neuron connections. So somehow, ketamine and the stress hormone cortisol work together to activate microglia. Activated microglia go all in on neighbouring neurons, triggering them to put out new connections.
Ketamine Triggers Female Return to Neuroplasticity
What does this mean for research into ketamine and neuroplasticity? It’s too early to tell, but knowing that cortisol is involved and which gene seems to be a gate keeper for the effect might set the scene for some very interesting new drugs. Is a wave of cortisol triggered in female brains as they start to wake up from ketamine sedation responsible for all these changes or is ketamine doing some other things too? Why do only female mice react like this? Could humans experience something similar?
It seems like it’s going to take a while for researchers to tie all these strands together. Maybe, though, it does suggest that something interesting is happening in our brains. Human clinical trials have hinted that ketamine works differently on women. Is this because of artefacts of experimental design? It’s a real possibility, since a lot of the ketamine trials aren’t as well controlled as they could be. One of the problems with ketamine – like other mind-bending drugs is that you can tell whether you are in the placebo group.
It’s very hard to get a handle on whether any apparent differences are to do with cell biology of the brain, because unlike mice, we can’t use lasers to look inside our brains while we are alive. For now, we’ll just have to see if improving and refining human ketamine trials will eventually give us some clues.
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