New research shows that miRNA135 may act as an endogenous antidepressant and that its levels in human blood can indicate clinical status as well as response to treatment, which brings us one step closer to better treatments for patients with Depression.
We all feel sad at times. In fact, it's a normal reaction to many of the challenges in life - loss, stress, and insult to name a few. While this feeling tends to go away, this is not always the case especially as depression, a feeling of sadness, becomes Depression, a mental illness that can disrupt daily life and may lead to suicide. Approximately 10 percent of people globally are affected by mood disorders like Depression making these disorders one of the most common health problems worldwide.
Unfortunately, current treatments for Depression tend to lack adequate efficacy with 60-70% of patients not experiencing remission while often requiring long periods of treatment before any relief is observed. This indicates that there is a great need for the development of better treatments, which is challenging since despite a large research effort, the molecular and cellular basis for its manifestation are only partially understood. What we do know is that serotonin levels play a role and this has been targeted by a major class of antidepressants, selective serotonin reuptake inhibitors (SSRIs), which act to restore these levels. Nonetheless, it is believed that a more detailed understanding of serotonin regulation will reveal novel targets that may produce better outcomes and can also serve as indicators of a treatment's efficacy, which could eliminate ineffective drug administration.
One current development in this area is the discovery that miR135 – a small 22 nucleotide-long RNA that can bind to the 3’-untranslated region of mRNA and promote its degradation – may act as an endogenous antidepressant as recently described in the journal Neuron.
The researchers identified this particular miRNA by looking at the miRNA “fingerprint” of serotonin-producing neurons compared to non-serotonin-producing neurons in mice via microarray. From this, they identified 91 miRNAs with expression levels at least 1.5-fold greater or less than non-serotonin-producing-neurons, and they used bioinformatics to predict which of these miRNA would target key serotonin-related genes. Studies of the prime candidates using a reporter system pointed to miR135 since it had a 30-50% repression of target transcripts.
Upon finding this miRNA and knowing the genes it modifies are associated with depression and antidepressant cellular machinery, they then wanted to see how antidepressants affect its expression. They looked at levels in mice in response to both chronic social defeat, a model to induce anxiety- and depression-like behaviors, as well as chronic treatment with antidepressants. While the social defeat model did not alter miR135 levels, chronic and acute administration of the antidepressant imipramine as well as fluoxetine, a SSRI, in both stressed and non-stressed mice significantly increased expression of miR135a while reboxetine, a noradrenaline reuptake inhibitor, had no effect.
They then looked further into the role of this miRNA using a recombinant mouse model that specifically overexpressed miRNA in serotonin neurons in a specific area of the brain called the dorsal raphe (RN). These mice had significant resiliency to chronic social defeat unlike their littermates with normal levels of the miRNA. Additionally, they knocked down the miRNA using a lentivirus-based system in wild type mice and found that these mice showed a significant increase in anxiety-like behavior compared to controls. These knock-down mice also were less sensitive to SSRI treatment. According to the paper, this suggests “an important role for endogenous RN-miRNA135 levels in mediating SSRI-induced anti-depressant effects.”
After this, they turned their focus toward human subjects by looking for miRNA levels in the blood. They found reduced levels of miR135 in currently depressed patients compared to controls and an increase in miR135a levels in depressed patients after 3 months of cognitive behavioral therapy though not after SSRI treatment. Therefore, they believe that this could serve as a biomarker for depression and response to treatment.
By first studying depression in mice then moving on to humans, these researchers identified miR135 as having a role in Depression since higher levels associate with resilience toward depression in mice as well as response to treatment. They believe it works by downregulating genes that are associated with serotonin metabolism thus producing a higher concentration of serotonin within synaptic clefts. While further study is needed particularly in humans, there is hope that this can lead to improved treatments that can provide relief for a greater number of people who suffer from Depression.
Image copyright: Jamey Cammell / flickr