Major depressive disorder (MDD) is characterized as a mood disorder that affects one's feelings, usually causing intense feelings of sadness and loneliness, isolation, loss of interest in one's life, and even suicidal ideation. MDD is one of the leading mental health crises and sadly contributes to the majority of disabilities and suicides in the world. MDD is not just a “state” of sadness as everyone experiences in their life, but rather possesses neural mechanisms that generate a person to feel depressed. However, there are no blood tests that can indicate molecular markers for disorders such as MDD, diagnosis is based strictly on questionnaires and evaluations; which can never be fully accurate and often overlap with other disorders. Therefore, researchers have spent years attempting to understand the mechanisms of MDD in hopes that more effective treatments can be developed to reduce the number of people struggling worldwide. While recent research has provided hopeful findings, there is still much left to be discovered about MDD, and a plethora of factors must be considered as major depressive disorder does not look the same for everyone.
Recent research by Sarawagi, et al. named, “Glutamate and GABA homeostasis and Neurometabolism in Major Depressive Disorder” analyzed the balance or homeostasis of neurotransmitters glutamate and GABA, and the processes involved in the production, usage, and degradation of these neurotransmitters in correspondence with those who have Major Depressive Disorder. The article first states how postmortem studies have found neuronal and glial cell loss in the cingulate cortex, prefrontal cortex, and hippocampus of those who were depressed. Genetics and epigenetic factors are thought to have a prominent influential role in the development of MDD, along with stress and environmental factors. Stress and the environment can place epigenetic markers such as DNA methylation or acetylation which can alter gene expression. Altered gene expression may impact neurotransmitter synthesis and homeostasis. Specifically, the central nervous system holds copious amounts of glutamate and GABA. The article characterizes depression as a deficit in different facets of reward. The brain’s reward system comprises the prefrontal cortex, nucleus accumbens, ventral tegmental area, amygdala, and hippocampus. These structures are conveniently interconnected via pathways of different neurotransmitters such as dopamine, serotonin, glutamate, and GABA. Hence, if MDD is a deficiency within the brain’s reward circuit, it would be logical to hypothesize that the mechanisms of MDD may be due to these neurotransmitters. Glutamate is the major excitatory neurotransmitter in the brain involved in signal transmission, neural processes, and learning and memory. GABA is the major inhibitory neurotransmitter of the brain. It functions in counteracting excitatory neurotransmitters such as glutamate and is also involved in learning and memory. The article points out that glutamate neurons compose about 80% of the synapses in the neocortex. Glutamate poses many functions within the brain, and can even indirectly drive gene expression through its binding to certain receptors that regulate mRNA. The article emphasizes that multiple animal and clinical studies have found dysfunction in the glutamatergic system in the brains of depressed subjects. Additionally, studies also found that there is decreased expression of glutamate receptors NMDA and AMPA in depressed individuals and those who committed suicide. Decreased expression of these receptors leads to problems in plasticity, learning, and memory, neural circuit activity of the whole brain, and throws off the homeostatic balance of neurotransmitters in the brain. Without a proper balance of excitatory and inhibitory neurotransmitters optimal operation of the brain is not possible. The article touches briefly on antidepressants to treat MDD as well, such as selective serotonin reuptake inhibitors which increase monoamine transmitters within the brain. It also mentions a new drug ketamine. Ketamine blocks the NMDA receptors of GABA neurons, which hinders the neurons’ capability for inhibition, and thus could work to stabilize neurometabolic activity of glutamate and GABA neurons. In conclusion, the article postulates that decreased glutamate and GABA neurotransmission along with diminished expression of receptors and imbalances of such neurotransmitters is thought to be a major underlying cause of MDD progression.
Additionally, a similar study called, “Sex differences in the transcription of glutamate transporters in major depression and suicide” by Powers, et al. accepts the hypothesis that glutamate imbalance underlies MDD. However, it emphasizes glutamate transporter gene expression and epigenetics as a primary factor while also accenting the sex differences present in those with MDD. In this article, they test their hypothesis that glutamate transporter gene expression is abnormal in the dorsolateral prefrontal cortex (DLPFC) of those with MDD. They assert the fact that women are two to three times more likely to be diagnosed with major depressive disorder and show more severe symptoms. To test their hypothesis the researchers measured the expression of vesicular glutamate transporters and excitatory amino acid transporters in post-mortem brains of MDD patients, some of whom died by suicide. Glutamate and amino acid transporters function to release and recycle glutamate. Their research found abnormal glutamatergic gene expression in the dorsolateral prefrontal cortex. Interestingly, they only found this in females and not males. However, both males and females exhibited DLPFC dysfunction. Revealing that there are possible molecular differences between males and females who both have MDD. The author notes that this could be due to the activity of estrogen in females in response to stress. Estrogen activates responses in the prefrontal cortex that may lie upstream of amino acid transporters genomically. This may upregulate amino acid transporters which could cause excess glutamate to be removed. Furthermore, abnormal gene expression of glutamate transporters could lead to atypical amounts of glutamate in the brain, and high levels of glutamate can lead to neuronal and glial cell death. The publication articulates that a possible explanation for altered gene expression could be due to environmental stressors and epigenetics. Stress and life circumstances can alter DNA through acetylation and methylation which can lead to permanent changes in gene expression—possibly clarifying a cause for the abnormal gene expression of glutamate transporters in the DLPFC. Irregular activity of the DLPFC leads to impairments in executive functioning and problem-solving, which is seen in those with MDD. The researchers also discuss finding alternative therapies to MDD by modulating glutamatergic transmission using ketamine as well, as it produces antidepressant effects in the prefrontal cortex. They also address another therapy that has been promising for MDD which is transcranial magnetic stimulation (TMS). While the exact mechanisms by which TMS works are not fully known it is thought that the magnetic fields can stimulate cells to influence the release of different neurotransmitters, it may also be able to help regulate abnormal brain activity and perhaps excite regions of the brain to improve mood.
In conclusion, the convergence of results from the two articles reveals that disruptions and imbalances of glutamate homeostasis within critical areas of the brain may underlie the manifestation of major depressive disorder. The first article portrays its findings by analyzing the contrasting levels of glutamate in different parts of the brain in comparison with GABA which inhibits glutamate. The second article goes a step deeper by analyzing if abnormal gene expression of glutamate transporters is a factor for high glutamate levels in brain areas of those with MDD that show dysfunction. Furthermore, the second article highlights the sex differences present in their findings with those who have MDD. Both articles present new therapies for MDD that show promising antidepressant effects that are not typical antidepressants. Further research on the neural mechanisms of major depressive disorder is essential to advance our understanding, generate advanced diagnostics, and better recognize how MDD coexists with other mental health disorders. Further research will allow targeted medical approaches to be uncovered that can vastly improve the quality of life of those with MDD, hopefully, one day decreasing the large number of people who are diagnosed worldwide.
References
Powers, B., Joyce, C., Kleinman, J. E., Hyde, T. M., Ajilore, O., Leow, A., & Sodhi, M. S. (2020). Sex differences in the transcription of glutamate transporters in major depression and suicide. Journal of affective disorders, 277, 244–252. https://doi.org/10.1016/j.jad.2020.07.05
Sarawagi, A., Soni, N. D., & Patel, A. B. (2021). Glutamate and GABA Homeostasis and Neurometabolism in Major Depressive Disorder. Frontiers in psychiatry, 12, 637863. https://doi.org/10.3389/fpsyt.2021.637863
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