Fear Processing in Mice with PMAT Deficiency

Abstract

The plasma membrane monoamine transporter (PMAT, Slc29a4) is a polyspecific cation transporter that, in the brain, predominantly takes up monoamine neurotransmitters like dopamine and serotonin. PMAT function is hypothesized to emerge when other monoamine transporter function is impaired, such as under conditions of heightened monoamine neurotransmitter release in response to stressors. In humans, common genetic polymorphisms can reduce PMAT function, but these have exclusively been studied in the context of metformin treatment response under diabetic conditions. Nothing is currently known about how reduced PMAT function affects fear processing, nor any other aspects of emotional learning or memory. Our lab sought to begin examining the effects of PMAT deficiency on fear processing by using mice with constitutive reductions in PMAT function (i.e., heterozygotes) and comparing these to wildtype mice. Specifically, we evaluated both cued and contextual fear processing. Based on evidence that chronic pharmacological blockade of serotonin transporter‐mediated monoamine uptake decreased both cued and contextual fear expression, we hypothesized heterozygote mice would display lower levels of both cued and contextual fear relative to wildtypes. Surprisingly, we only observed a trend (p=0.08) specifically in male heterozygotes for attenuated cued fear expression. Otherwise, heterozygotes of both sexes exhibited cued fear acquisition, extinction retention, and renewal that was indistinguishable from wildtypes, as was their contextual fear processing. Four weeks after fear processing behavior tests concluded, mice were subjected to a brief swim stress, and blood was collected for stress hormone quantification. These data are currently being analyzed, and we hypothesize that heterotypic stressor exposure will unmask the behavioral sequelae of reduced PMAT function. Our current findings are consistent with previous reports of sex‐selective effects of PMAT deficiency on behavioral responses to stressor exposure. Continued investigation into how reduced PMAT function affects emotion processing and stress responsivity could have translational implications for people with functional PMAT polymorphisms.