A team of researchers at the University of Pennsylvania School of Medicine have published findings which show how ketamine dramatically reorganises activity in the brain – as if a switch had been flipped on its active circuits.
The researchers described changed neuronal activity patterns in the cerebral cortex of animal models after ketamine administration — observing normally active neurons that were silenced and another set that were normally quiet suddenly springing to action.
This ketamine-induced activity switch in key brain regions tied to depression may impact our understanding of ketamine’s treatment effects and future research in the field of neuropsychiatry, according to the researchers.
Co-lead and co-senior author, Joseph Cichon, MD, PhD, an assistant professor of Anesthesiology and Critical Care and Neuroscience in the Perelman School of Medicine at the University of Pennsylvania, stated: “Our surprising results reveal two distinct populations of cortical neurons, one engaged in normal awake brain function, the other linked to the ketamine-induced brain state.
“It’s possible that this new network induced by ketamine enables dreams, hypnosis, or some type of unconscious state. And if that is determined to be true, this could also signal that it is the place where ketamine’s therapeutic effects take place.”
The study has been published in Nature Neuroscience.
Ketamine and brain activity
Ketamine has been a mainstay in anaesthesia practice because of its reliable physiological effects and safety profile.
One of ketamine’s signature characteristics is that it maintains some activity states across the surface of the brain compared with most other anaesthetics, which work by totally suppressing brain activity.
It is these preserved neuronal activities that are thought to be important for ketamine’s antidepressant effects in key brain areas related to depression, however, how ketamine exerts these clinical effects remains unknown.
For this study, the researchers analysed mouse behaviours before and after they were administered ketamine, comparing them to control mice who received placebo saline.
They found that those given ketamine exhibited behavioural changes consistent with what is seen in humans on the drug, including reduced mobility, impaired responses to sensory stimuli, which are collectively termed “dissociation.”
Co-lead and co-senior author Alex Proekt, MD, PhD, an associate professor of Anesthesiology and Critical Care at Penn, commented: “We were hoping to pinpoint exactly what parts of the brain circuit ketamine affects when it’s administered so that we might open the door to better study of it and, down the road, more beneficial therapeutic use of it.”
Using two-photon microscopy to image cortical brain tissue before and after ketamine treatment, the team followed individual neurons and their activity finding that ketamine turned on silent cells and turned off previously active neurons.
The neuronal activity observed was traced to ketamine’s ability to block the activity of synaptic receptors called NMDA receptors and ion channels called HCN channels.
To add to this, the team found that they could recreate ketamine’s effects without the medications by simply inhibiting these specific receptors and channels in the cortex.
The scientists showed that ketamine weakens several sets of inhibitory cortical neurons that normally suppress other neurons. This allowed the normally quiet neurons, the ones usually being suppressed when ketamine wasn’t present, to become active.
This dropout in inhibition was necessary for the activity switch in excitatory neurons — the neurons forming communication highways, and the main target of commonly prescribed antidepressant medications.
Co-author Max Kelz, MD, PhD, a distinguished professor of Anesthesiology and vice chair of research in Anesthesiology and Critical Care, added: “While our study directly pertains to basic neuroscience, it does point at the greater potential of ketamine as a quick-acting antidepressant, among other applications,” said
“Further research is needed to fully explore this, but the neuronal switch we found also underlies dissociated, hallucinatory states caused by some psychiatric illnesses.”
