Novel gene target reveals antidepressant mechanism of electroconvulsive therapy

Written by Roisin Conneely

A study from John Hopkins Medicine (MD, USA) has demonstrated that electroconvulsive therapy (ECT) may aid depression symptoms by acting upon a novel target, the immediate early gene Narp within the hippocampus.

Previous work has highlighted how genes, including Narp, are turned on in the hippocampus within minutes of ECT.

The team utilized healthy mice and genetically engineered Narp knockouts to compare the influence of the encoded NARP protein during ECT. The two groups were given ECT and then subjected to the forced swim test, a behavioural test to assess depression levels, as more depressed mice will spend longer periods floating as opposed to swimming. The test lasted for 6 minutes, with healthy mice only floating for 50 seconds of the last 4 minutes, whilst mice lacking Narp spent 80 seconds floating.

The results suggest that Narp is a specific target necessary for ECT to administer antidepressant effects. Although several studies have indicated ECT as a useful treatment for depression, concerns have been raised about side effects such as memory loss. Understanding the mechanisms of ECT and the molecular targets involved may pave the way for improved application of the treatment.

Evidence has already demonstrated that within weeks of ECT or undergoing successful antidepressant therapy, stem cells in the hippocampus begin to generate more hippocampal neurones. The team decided to investigate whether Narp played a role in this proliferation, by injecting a synthetic molecule, BrdU to label and detect newly-formed cells. Both healthy and knockout mice were found to have three-times the number of new neurones in the hippocampus after being given ECT compared with mice undergoing sham ECT.

Dendrites from these new cells were also examined by staining for the protein DCX. Within 24 hours of ECT, Narp knockout mice were observed to have fewer dendritic branches on new cells in comparison with the healthy mice. This indicates that the protein also plays a role in communication between neurones, which may further explain its antidepressant influence during ECT.

To conclude their investigation into Narp, researchers tested healthy mice to examine how they responded to ketamine as an antidepressant. Utilizing the forced swim test, they determined that the absence of Narpdoes not influence the response to ketamine, implying that the drug brings about antidepressant effects via a different mechanism to ECT, highlighting the multiple pathways that may be utilized in depression therapy.

Sources:  Chang AD, Vaidya PV, Retzbach EP et al. Narp Mediates Antidepressant-Like Effects of Electroconvulsive SeizuresNeuropsychopharmacology. doi:10.1038/npp.2017.252 (2017) (Epub ahead of print);