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Yale Study: Ketamine Disinhibits Dendrites and Enhances Calcium Signals in Prefrontal Dendritic Spines

January 07, 2020

A single dose of ketamine exerts antidepressant effects within several hours and lasts for two weeks. One striking consequence of ketamine administration in an animal model is an increase in the number of neuronal connections, as reflected by an increase in the number of dendritic spines in the prefrontal cortex.

This observation has fueled the idea that neural plasticity may underlie the long-lasting behavioral effects. However, the neural mechanisms that are responsible for ketamine’s propensity to induce synapse formation remain incompletely understood.

In a new study published January 7, 2019 in Nature Communications, Alex Kwan, PhD, Associate Professor of Psychiatry and his research team used subcellular-resolution two-photon microscopy to visualize calcium ions in dendritic spines in the live mouse brain. The calcium signals are important because the concentration of calcium ions is elevated when a synapse is activated, and therefore calcium is a proxy of the responsiveness of the neuronal connection.

Kwan and his team found that within an hour after a mouse received ketamine, there is a substantial increase in the amount of calcium that goes into the dendritic spines for neurons in the prefrontal cortex.

“We were puzzled by the data, because we originally expected to see a decrease in the synaptic calcium signal in response to ketamine,” said Kwan, the paper's senior author.

His reasoning was based on ketamine being a compound that selectively blocks N-methyl-D-aspartate (NMDA) receptors, ion channels that normally let calcium flow into the dendritic spines.

So why would blocking a calcium-permeable channel have the final effect of raising calcium? To answer this question, Kwan and his team did a series of experiments to show that ketamine not only affects the principal pyramidal neurons, but also markedly reduces the activity of a subclass of GABAergic neurons that normally inhibit dendrites.

These results provide evidence for a two-step model – ketamine would decrease the activity of dendrite-targeting GABAergic neurons, which then, in turn, disinhibits the dendritic spines and therefore allows for more calcium influx.

Kwan and his team think the finding has implications for finding and evaluating new compounds that may also have rapid-acting antidepressant effects.

“There is a long history of studies showing a direct relationship between calcium signaling in a dendritic spine and the subsequent plasticity process," Kwan said. "What we see here for ketamine may be the tip of an iceberg, and we speculate that the calcium rise at the synapses could be also true for other plasticity promoting compounds.”

The first author of the study is Farhan Ali, PhD, a postdoctoral associate in the Department of Psychiatry. Collaborators include Ronald Duman, PhD, Elizabeth Mears and House Jameson Professor of Psychiatry and Professor of Neuroscience, and Christopher Pittenger, MD, PhD, Associate Professor of Psychiatry.

Submitted by Christopher Gardner on January 07, 2020