Defining the Role of the 5-HT4 Receptor in the Brain, Behavior, and Gut Abnormalities Resulting from In Utero SSRI Exposure

Depression during pregnancy is a common and serious issue both in military and civilian populations. Depression affects 10% of women nationally, and > 30% of female military members (Soldiers, spouses and their beneficiaries). The majority of active female Soldiers and military spouses are of childbearing age. During pregnancy, mental illness increases an additional > 30%, and depression is among the top three of these diagnoses. Untreated depression in pregnancy is associated with negative long-lasting developmental outcomes in children, including an increased risk in anxiety and depression; decreased cognition, learning, and social functioning; and consequences on overall health, rendering treatment of depression during pregnancy critical not just for the health of the mother but also for the health of the child.

Selective serotonin reuptake inhibitors (SSRIs) are used in up to 8% of pregnancies nationwide and are the most widely prescribed antidepressants prescribed to pregnant female military personnel. Further, SSRIs are also commonly used to treat anxiety and post-traumatic stress disorder, two conditions that are prevalent in female military members and present in even higher proportions in those that are pregnant. SSRIs are often considered first-line treatment because of their relative safety compared to other antidepressants. Unfortunately, SSRI exposure during pregnancy has also been associated with negative consequences to the child, such as behavioral disorders (i.e., anxiety and depression) as well as abnormalities in brain and intestinal development that plague affected children long-term. Therapies do not exist that reverse the detrimental effects of perinatal SSRI exposure to the brain, intestine, and behavior.

There is a lifelong continuous communication that occurs between the intestine, the brain, and the intestinal bacteria (the microbiome). These interactions, termed the 'brain-gut-microbiome (BGM) axis,' play critical roles in the way the brain and intestine develop and function, as well as in how behavior evolves. Intriguingly, the BGM axis modulates many parameters that develop abnormally in children exposed to SSRIs perinatally, which indicates that it could play a critical role in causing functional deficits such as, constipation, anxiety, depression, and cognitive impairment. Although it is evident that SSRIs impact the BGM axis, it is not yet possible to decipher these interactions in developing humans. Mice display pharmacokinetics and pharmacodynamics for perinatal SSRI exposure that parallel the human situation, making them an ideal model to study BGM interactions in the context of perinatal SSRI exposure. Indeed, we have recently created a mouse model of perinatal SSRI exposure that mimics the intestinal and behavioral traits demonstrated in children exposed to SSRIs perinatally, making an in-depth analysis of the interplay between SSRIs and the BGM axis now feasible. Further, we have utilized this model to demonstrate that treatment with a serotonin 4 receptor (5-HT4) antagonist, piboserod, in the perinatal period, can prevent the intestinal, behavioral, and intestinal microbiota abnormalities induced by perinatal SSRI exposure. Piboserod is thus a potentially novel medical treatment to reverse the BGM abnormalities associated with perinatal SSRI exposure. This is the only study, to our knowledge, that aims to understand the influences of perinatal SSRI exposure on the BGM axis, tests a treatment for such disorders, and paves the way for the creation of novel therapies that can treat the BGM dysfunction that arises from perinatal SSRI exposure. The first part of this study will investigate brain regions that SSRIs and piboserod affect so that they may be targeted for future therapeutic development for brain-gut axis disorders. In the second part, we will determine whether piboserod can reverse the abnormalities in the brain and intestine once they have occurred. This is important because we have thus far only demonstrated that piboserod can prevent such abnormalities if given perinatally, but BGM axis disorders are not diagnosed until after the perinatal period. We will determine whether piboserod can reverse the BGM abnormalities in ages equivalent to childhood and adolescence. Finally, we will use newly created mice to determine whether brain, intestine, microbiota, or behavioral anomalies stem from SSRI influence on the brain or the intestine. This will provide a foundation upon which novel drugs that are specifically targeted to brain or intestine can be created to treat specific aspects of BGM dysfunction.

This application addresses 'areas of encouragement' requested for this grant mechanism that are listed under 'psychotropic medications.' These include (1) research that evaluates the use of psychotropic medications for mental health issues specific to women in the military and (2) the identification and/or development of therapies that can completely or selectively reverse the effects of psychotropic medications. In the short-term, these aims test a completely novel therapy to reverse the BGM consequences of perinatal SSRI exposure. In the long-term, an enhanced understanding of SSRIs and BGM axis interactions will improve approaches towards treating depression during pregnancy and provide therapeutic targets for correcting BGM axis dysfunction.