Differential consequences of early SSRI exposure upon the developing nervous system of Xenopus laevis

Abstract

Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for maternal depression, one of the most prevalent perinatal psychiatric conditions. Although the effects of maternal depression have been well‐characterized, there exists controversy over the adverse effects of SSRI use upon fetal development. Few studies have adequately isolated outcomes due to SSRI exposure and those due to maternal psychiatric conditions. Here, we narrowed our focus to investigating the outcomes of exposure to the widely‐used SSRIs fluoxetine (Prozac) and citalopram (Celexa) upon the developing nervous system through behavioral and electrophysiological assays in Xenopus laevis. Exposure concentrations and timelines in humans were translated to the X. laevis using standard dosages and dose‐response curves. Behavioral assays and whole‐cell patch‐clamp recording were performed at full maturation (stage 49). The behavioral paradigms of acoustic startle habituation and seizure susceptibility in pentylenetetrazol have established relevance to autism‐like phenotypes in X. laevis and normal neurodevelopment. Interestingly, the two SSRIs demonstrated differential abnormalities in behavior and properties of the neuron and synaptic transmission. Administration of fluoxetine during development resulted in slower habituation and increased seizure susceptibility, while exposure to citalopram led to faster habituation and decreased seizure susceptibility. We sought to explain these opposing behavioral phenotypes by whole‐cell patch‐clamp recording from the sensory‐processing tectum. We found that tectal neurons from fluoxetine‐treated animals demonstrated increased intrinsic excitability and those from citalopram‐treated animals showed decreased excitability. Moreover, citalopram‐treated neurons had increased spontaneous excitatory post‐synaptic current episodes, indicating stronger individual synaptic transmission and stronger synaptic drive. Neither group showed altered synaptic facilitation, a neurobiological mechanism related to plasticity and learning, nor an imbalance of excitatory and inhibitory projections, a circuit‐level property associated with normal neurodevelopment. These results not only support the potential role of SSRIs upon the developing brain at both the behavioral and biological levels, but complicate the discretion to administer either antidepressant. Our findings implicate the off‐target effects of fluoxetine to explain such opposing consequences, given the higher selectivity of citalopram for the serotonin reuptake transporter. Future studies will systematically probe other monoamine transporters, including those for norepinephrine and dopamine, and serotonin receptors, both of which are affected by fluoxetine. This project was funded by the American Physiological Society.Support or Funding InformationThe American Physiological SocietyThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.