Summary: A new computer model reveals how ketamine, a widely used anesthetic and antidepressant, affects brain activity. By simulating the drug’s interaction with NMDA receptors, the model explains how ketamine alters neuronal firing patterns, leading to altered states of consciousness and potential therapeutic benefits for depression.
Highlights:
- Ketamine blocks NMDA receptors in the cerebral cortex, impacting neuronal communication.
- The model accurately reproduces real brain waves and neuronal spikes observed in humans and animals on ketamine.
- The results suggest a possible mechanism for ketamine’s antidepressant effects through increased gamma activity.
Source: MIT
A World Health Organization essential medicine, ketamine is widely used in varying doses for sedation, pain control, general anesthesia, and as a treatment for treatment-resistant depression.
Although scientists know its target in brain cells and have observed how it affects brain-wide activity, they don’t know exactly how the two are linked.
A new study by a research team spanning four Boston-area institutions uses computer modeling of previously little-known physiological details to fill this gap and offer new insights into how ketamine works.
“This modeling work helped decipher the likely mechanisms by which ketamine produces altered arousal states as well as its therapeutic benefits for treating depression,” co-senior author Emery N. Brown, the Edward Hood Taplin Professor of Computational Neuroscience and medical engineering at the Picower Institute. for Learning and Memory at MIT, as well as an anesthesiologist at MGH and professor at Harvard Medical School.
The researchers from MIT, Boston University, Massachusetts General Hospital and Harvard University said their model’s predictions, published May 20 in Proceedings of the National Academy of Sciencescould help doctors use the drug better.
“When doctors understand what’s happening mechanically when they administer a drug, they can potentially exploit that mechanism and manipulate it,” said the study’s lead author, Elie Adam, a research scientist at MIT who will soon join the Harvard Medical School and will launch a laboratory at MGH.
“They learn how to enhance the good effects of the drug and how to mitigate the bad ones.”
Block the door
The main advance of the study was to biophysically model what happens when ketamine blocks “NMDA” receptors in the cerebral cortex, the outer layer where key functions such as sensory processing and cognition take place. Blocking NMDA receptors modulates the release of glutamate, an excitatory neurotransmitter.
When neural channels (or gates) regulated by NMDA receptors open, they usually close slowly (like a door with a hydraulic closer that keeps it from slamming), allowing ions to flow in and out of the neurons, thus regulating their electrical properties. Adam said.
However, the receptor channels can be blocked by a molecule. Blocking with magnesium helps to naturally regulate ionic flow. Ketamine, however, is a particularly effective blocker.
Blocking slows the build-up of voltage across the neuron’s membrane, eventually leading a neuron to “spike” or send an electrochemical message to other neurons. The NMDA gate unlocks when the voltage becomes high.
This interdependence between voltage, spiking, and gating may endow NMDA receptors with faster activity than its slow closing rate suggests. The team’s model goes further than previous ones by representing how blocking and unblocking ketamine affects neuronal activity.
“Physiological details that are typically ignored can sometimes be critical to understanding cognitive phenomena,” said co-corresponding author Nancy Kopell, a professor of mathematics at BU.
“NMDA receptor dynamics have more impact on network dynamics than previously appreciated.”
With their model, the scientists simulated how different doses of ketamine affecting NMDA receptors would change the activity of a model brain network.
The simulated network included key neuron types found in the cortex: one excitatory type and two inhibitory types. He distinguishes between “tonic” interneurons which slow down the activity of the network and “phasic” interneurons which react more to excitatory neurons.
The team’s simulations successfully recapitulated the actual brain waves that were measured via EEG electrodes on the scalp of a human volunteer given various doses of ketamine and the neuronal spikes that were measured in animals treated with the same way and having implanted electrode arrays.
At low doses, ketamine increased brain wave power in the fast gamma frequency range (30 to 40 Hz). At higher doses that cause loss of consciousness, these gamma waves are periodically interrupted by “low” states where only very slow frequency delta waves occur.
This repeated disruption of higher frequency waves is what can disrupt communication through the cortex enough to disrupt consciousness.
But how? Main findings
Importantly, through simulations, they explained several key network mechanisms that would produce exactly these dynamics.
The first prediction is that ketamine may disinhibit network activity by shutting down certain inhibitory interneurons. Modeling shows that the natural blocking and unblocking kinetics of NMDA receptors can allow a small current to pass when neurons are not spiking.
Many neurons in the network that are at the right level of excitation would rely on this current to increase spontaneously. But when ketamine alters the kinetics of NMDA receptors, it turns off this current, leaving these neurons suppressed. In the model, although ketamine impairs all neurons equally, it is the tonic inhibitory neurons that are shut down because they are at this level of excitation.
This frees other neurons, excitatory or inhibitory, from their inhibition, allowing them to grow vigorously and leading to a ketamine-excited brain state. The increased excitation of the network can then allow rapid unblocking (and reblocking) of the neurons’ NMDA receptors, causing bursts of spikes.
Another prediction is that these bursts will synchronize with the gamma frequency waves observed with ketamine. How? The team discovered that phasic inhibitory interneurons are stimulated by copious inputs of the neurotransmitter glutamate from excitatory neurons and fire vigorously.
When they do, they send an inhibitory signal from the neurotransmitter GABA to excitatory neurons that quells excitatory firing, almost like a kindergarten teacher calming down an entire class of excited children.
This stop signal, which reaches all excitatory neurons simultaneously, lasts only a certain amount of time and eventually synchronizes their activity, producing a coordinated gamma brain wave.
“The finding that an individual synaptic receptor (NMDA) can produce gamma oscillations and that these gamma oscillations can influence gamma at the network level was unexpected,” said co-corresponding author Michelle McCarthy, research assistant professor of mathematics at BU.
“This was only discovered using a detailed physiological model of the NMDA receptor. This level of physiological detail revealed a gamma time scale that is not typically associated with an NMDA receptor.
So what about the periodic states of depression that appear at higher doses of ketamine and induce loss of consciousness? In the simulation, the gamma frequency activity of excitatory neurons cannot be sustained for too long by the altered kinetics of NMDA receptors.
Excitatory neurons become exhausted primarily under GABA inhibition by phasic interneurons. This produces the shutdown state. But then, after they stop sending glutamate to phasic interneurons, these cells stop producing their inhibitory GABA signals. This allows the excitatory neurons to recover and start a new cycle.
A link with antidepressants?
The model makes another prediction that could help explain how ketamine exerts its antidepressant effects. This suggests that the increased gamma activity of ketamine could lead to gamma activity among neurons expressing a peptide called VIP. This peptide has been shown to have health benefits, such as reducing inflammation, that last much longer than ketamine’s effects on NMDA receptors.
The research team proposes that training these neurons under ketamine could increase the release of the beneficial peptide, as observed when these cells are stimulated in experiments. This also hints at therapeutic characteristics of ketamine that could go beyond antidepressant effects.
The research team acknowledges, however, that this link is speculative and awaits specific experimental validation.
“Understanding that subcellular details of the NMDA receptor can lead to increased gamma oscillations formed the basis of a new theory of how ketamine might work in the treatment of depression,” Kopell said. .
Other co-authors of the study are Marek Kowalski, Oluwaseun Akeju and Earl K. Miller.
Funding: The JPB Foundation, the Picower Institute for Learning and Memory, the Simons Center for The Social Brain, the National Institutes of Health, George J. Elbaum (MIT ’59, SM ’63, PhD ’67), Mimi Jensen, Diane B. Greene (MIT, SM ’78), Mendel Rosenblum, Bill Swanson, and annual donors to the Anesthesia Initiative Fund supported the research.
About this research news on ketamine and neuroscience
Author: David Orenstein
Source: MIT
Contact: David Orenstein – MIT
Picture: Image is credited to Neuroscience News
Original research: Closed access.
“Ketamine may produce oscillatory dynamics by engaging mechanisms dependent on NMDA receptor kinetics” by Emery N. Brown et al. PNAS
Abstract
Ketamine can produce oscillatory dynamics by engaging mechanisms…
News Source : neurosciencenews.com
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