Our lab is uncovering some of the factors that lead to depression and determine whether patients will respond to antidepressants. Since antidepressants (e.g., serotonin-specific reuptake inhibitors (SSRIs)) are only effective in 30% of depressed patients and require over three weeks. Thus, better ways of predicting response or alternative treatments are needed. To address these questions, we have examined the genetic and epigenetic regulators of the serotonin system and their effects on behavior and antidepressant response. To do this we use mouse models of mental illness, as well as human samples from collaborators.

We have focused on the serotonin-1A (5-HT1A) receptor gene. As an autoreceptor on serotonin neurons, the 5-HT1A negatively regulates their activity and is associated with depression and resistance to SSRIs. But as a heteroreceptor on post-synaptic target neurons, it mediates serotonin actions (see Figure). In addition, the 3-week delay in response to SSRIs reflects the time it takes to desensitize the 5-HT1A autoreceptors. Therefore, we first identified the molecular mechanisms that regulate the 5-HT1A and serotonin genes. We identified key DNA elements that regulate these genes and cloned their transcription factors. We also identified an interesting human DNA variant (rs6295) that increases 5-HT1A expression and is associated with SSRI-resistant depression. To test whether these transcription changes really affect depression we knocked them out in serotonin neurons of adult mice. This results in SSRI-resistant anxiety and depression-like behaviors. We are now testing whether other types of antidepressants or direct stimulation of serotonin neurons will reverse the depression in these mice.

In addition to genetic changes, we examine how stress affects behavior and response to antidepressants. We find important roles of DNA methylation, RNA splicing, and micro-RNA regulation of the 5-HT1A gene in these depression models and in humans. We have also established a new mouse model of post-stroke depression that responds to SSRI treatment but not exercise. Using this injury model of depression, we are finding that SSRIs enhance neuroplasticity for long-lasting recovery from depression. By understanding antidepressant actions in these models, we can develop better treatment strategies for depression in humans.

Five Key Publications

Albert lab members in bold
Publications archived at: ResearchGate

1. Turcotte-Cardin V, Vahid-Ansari F, Luckhart C, Daigle M, Geddes SD, Tanaka KF, Hen R, James J, Merali Z, Beique JC, Albert PR (2019) Loss of adult 5-HT1A autoreceptors results in a paradoxical anxiogenic response to antidepressant treatment. J Neurosci 39, 1334-46. PDF

2. Le François B, Zhang L, Mahajan GJ, Stockmeier C, Friedman E, Albert PR (2018) A novel alternative splicing mechanism that enhances human 5-HT1A receptor RNA stability is altered in major depression. J Neurosci 38, 8200-10. PDF

3. Vahid-Ansari F, Daigle M, Manzini MC, Tanaka KF, Hen R, Geddes SD, Beique JC, James J, Merali Z, Albert PR. (2017) Abrogated Freud-1/CC2D1A repression of 5-HT1A autoreceptors induces fluoxetine-resistant anxiety/depression-like behavior. J Neurosci 37, 11967-11978. PDF

4. Zahrai A, Vahid-Ansari F, Daigle M, Albert PR (2020) Fluoxetine-induced recovery of serotonin and norepinephrine projections in a mouse model of post-stroke depression. Transl Psychiatry 10:334. PDF

5. Vahid-Ansari F and Albert PR (2018) Chronic fluoxetine induces activity changes in recovery from post-stroke anxiety, depression and cognitive impairment. Neurotherapeutics 15, 200-215. PDF.