In a groundbreaking study led by Dr. Chen Yelin from the Shanghai Institute of Organic Chemistry of the Chinese Academy of Sciences, researchers have pinpointed GluN2A, a subunit of the N-methyl-d-aspartic acid (NMDA) receptor, as critical to the rapid antidepressant effects induced by ketamine.
The study, published in Nature Neuroscience, challenges conventional theories and introduces new pathways for the development of fast-acting, safer antidepressants.
The Challenge of Depression Treatment
Depression impacts approximately 10% of the global population and poses numerous treatment challenges.
Traditional antidepressants often have delayed responses, are ineffective for around 30% of patients, and don’t mitigate the risk of suicide.
While Esketamine (Spravato), a fast-acting antidepressant, has shown promise, it also brings with it risks such as addiction and psycho-stimulant side effects.
Role of GluN2A
The study revealed that germline knockout of GluN2A in mice triggered both psycho-mimetic and antidepressant-like behaviors.
Intriguingly, the depletion of GluN2A in adult mice induced antidepressant effects without the psycho-mimetic side effects. This indicates that targeting GluN2A could offer a safer route for treating depression.
Separating Antidepressant and Psycho-stimulant Effects
Further studies found that the antidepressant effects of ketamine and MK-801 were completely abolished in mice lacking GluN2A, while the psycho-stimulant effects remained.
This suggests that GluN2A is specifically necessary for the antidepressant effects, separating it from the psycho-stimulant side effects.
Challenging Established Beliefs
Contrary to widely held views that ketamine acts on inhibitory neurons to produce its antidepressant effects, this study found that the knockout of GluN2A in excitatory neurons of the cortex and hippocampus replicated the antidepressant behaviors.
Even more surprising, removing GluN2A in just the hippocampal neurons alone was sufficient to induce antidepressant-like effects.
Electrophysiological Findings
The study also included electrophysiological investigations which revealed that the loss of GluN2A significantly increased the intrinsic excitability of hippocampal excitatory neurons.
This aligns closely with the observed behavioral phenotypes, highlighting the critical role of GluN2A in mediating the antidepressant-like effects induced by ketamine.
Implications for Future Treatments
The findings from this study open up a new avenue for the development of fast-acting antidepressants with potentially fewer side effects, by targeting GluN2A.
This could revolutionize treatment for depression, offering hope for the many patients for whom current therapies are ineffective.
“Understanding the role of GluN2A in mediating the rapid antidepressant effects is a huge step forward in the fight against depression,” said Dr. Chen Yelin.
“This could be the key to developing safer, more effective treatments for this debilitating condition.”
If you care about health, please read studies that scientists find a core feature of depression and this metal in the brain strongly linked to depression.
For more information about health, please see recent studies about drug for mental health that may harm the brain, and results showing this therapy more effective than ketamine in treating severe depression.
The research findings can be found in Nature Neuroscience.
Follow us on Twitter for more articles about this topic.
Copyright © 2023 Knowridge Science Report. All rights reserved.
