New brain cells developed in the brain hippocampus after electroconvulsive therapy in a healthy mouse (top) and a Narp protein-deficient mouse (bottom). New cells from Narp-deficient mice had fewer branching dendrites, which are necessary for communication with nearby brain cells, than healthy mice.
Credit: Irving Reti laboratory
Sharing the Quick Truth
In a study using genetically engineered mice, Johns Hopkins researchers discovered some new molecular details that can be found to explain how electroconvulsive therapy (ECT) can quickly relieve severe depression. in mammals, perhaps including humans. Molecular changes allow a lot of communication between neurons in a specific part of the brain that are also known to respond to antidepressant drugs.
A report on their study, published online on October 20 at Neuropsychopharmacology, the researchers said the findings should help drive the progression of treatments that do what ECT does without the risks and side effects.
“ECT is the most effective treatment available for severe and uncontrollable depression treatment, but it requires anesthesia and can cause side effects such as memory loss,” he said. Irving Michael Reti, MBBS, MD, director of the Brain Stimulation Program and associate professor of psychiatry and behavioral sciences at Johns Hopkins University School of Medicine. “Thinking about how accurate ECT is in the brain is the key to finding better alternatives.”
The new study magnifies the work of Reti and her colleagues, whose research recently focused on a gene in the mouse brain hippocampus that produces the protein Narp, shown to be linked to addiction and called “ behavior inspired ”more than a decade ago, while Reti worked with Jay Baraban at Johns Hopkins.
ECT, given to patients with depression under anesthesia and after taking a muscle relaxer, sends electrical pulses to the brain through electrodes placed on the head. The stimulation of electricity provoked a seizure. Repeated several times a week over a short period of time, ECT removes symptoms of depression for a long time in many patients.
Working with mice, Reti and others have previously shown that within minutes of ECT, certain genes especially Narp are activated in the hippocampus, a small, sea -shaped part of the brain in the temporal lobe that help control emotions.
For the new study exploring Narp’s role in ECT, the researchers used healthy mice and mice that were genetically bred lacking Narp.
Mice in both groups were subjected to ECT for five sessions delivered via ear clip electrodes. Separately, the same variety of mice acquired “sham” methods without the electric pulse as controls. Each ECT session delivers a 0.5 millisecond electrical pulse for 1 second, with a frequency of 100 Hertz and 40 milliamps that is now about 5 percent of the total electrical charge provided by a human patient.
Next, the researchers measured the behavior of the mice using a well -known swimming test in which the animals were placed in a tank filled with water while the researchers examined how they finished swimming versus how they juice. to float.
A submerged mouse will spend more time floating just as giving active swimming than an unrestrained mouse. In the six -minute test, healthy mice spent about 50 seconds in the last four minutes floating, while mice without Narp spent about 80 seconds floating in this time frame.
The researchers said the results showed that Narp was a specific target needed for the effect of ECT as an antidepressant.
In both healthy mice and mice without Narp, ECT unlocked the c-Fos gene which is known to turn more ECT-activated genes within an hour after the last ECT session.
It is already known that a few weeks after an ECT procedure or after taking an effective antidepressant the stem cells in the hippocampus open up and make multiple copies of the hippocampal neurons.
To determine if Narp played a role in the formation of these new cells in mice, the researchers injected a synthetic molecule, BrdU, to mark and allow the newly created cells to be identified. cells that become neurons in the hippocampus. Both healthy mice and mice without Narp had three times the number of new cells in the hippocampus after ECT than mice given the sham method.
The researchers also looked at dendrites that grow from new brain cells, designs that come and communicate with neighboring cells. They look at dendrites by attaching them to the DCX protein, which binds to the cell skeleton. About 24 hours after the last ECT session in both healthy mice and Narp-deficient mice, they found that new cells in Narp-deficient mice had much smaller branches in their dendrites than cells found in the healthy hippocampus of mice.
“What we’ve all been told is that Narp seems to control communication with other neurons by making new synapses, or connections, and this could be in a way that, in part, it causes antidepressant effects that following ECT, “Reti said.
The researchers tested healthy mice to see if they responded to antidepressant medications. Using the forced swimming test, they found that mice given 10 milligrams per kilogram of injected ketamine floated about 75 seconds compared to 110 seconds for mice not given the drug. Researchers looked at mice without Narp to determine if they responded to ketamine. Mice not given Narp medication floated for about 110 seconds, while rats not dyup given ketamine floated for about 90 seconds.
“What this suggests is that the absence of Narp does not affect the ketamine response, meaning that the antidepressant may act through a different mechanism than ECT which suggests that there may be many ways to treat depression, including not known pathways that use the ECT mechanism, ”Reti said.
Other authors of the study included Andrew Chang, Punit Vaidya, Edward Retzbach, Sunho Chung, Urian Kim, Kathryn Baselice, Alec Stepanian, Melissa Staley, Lan Xiao, Ashley Blouin, Sungho Han, JohgAh Lee, Paul Worley, Kellie Tamashiro , Kerri Martinowich, Mary Ann Wilson and Jay Baraban from Johns Hopkins; Kristen Maynard of the Lieber Institute for Brain Development and Barbara Hempstead of Weill Cornell Medical College.
The study was funded by grants from the National Institute on Drug Abuse (R01 DA016303), National Institute of Neurological Disorders and Stroke (R01 NS039156), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54 HD079123) and Eric and Alison Jager.
COI: Reti and Vaidya received free supplies from Neuronetics, Inc. Reti is part of a TMS clinical trial with Brainsway, Inc. and the U.S. Department of Defense.