Toliver, A. | Search bioRxiv

bioRxiv2025

Human sensory neurons exhibit cell-type-specific, pain-associated differences in intrinsic excitability and expression of SCN9A and SCN10A

Despite major advances in pain science, the approval of novel therapeutics has been slow. A major cause for the lack of new analgesics may be fundamental biological differences between humans and model organisms used in preclinical research. Large-scale transcriptional profiling efforts on human dorsal root ganglia (hDRG) have now identified at least 22 distinct neuronal subtypes; however, a significant knowledge gap exists in ascribing functional phenotypes to these diverse neuronal populations. In this study, we use Patch-seq recordings in hDRG to link electrical properties to transcriptionally defined cell types. First, through unbiased clustering of electrophysiological properties from 228 hDRG neurons, we identify three electrophysiological subtypes (E-types). Next, we show that E-types can be mapped onto specific transcriptional classes (T-types) of hDRG neurons. We find that donors pain history is associated with E-type-specific differences in electrical properties, some of which may be associated with higher expression of voltage-gated sodium channels, NaV1.7 and NaV1.8. These results highlight the importance of using multimodal profiling to better understand human sensory neuron biology and may help reveal novel therapeutic targets driving chronic pain. TeaserMapping electrical properties to transcriptional profiles of human sensory neurons offers new insights into pain neurobiology

neuroscience↗

bioRxiv2019

Early developmental exposure to Fluoxetine and Citalopram results in different neurodevelopmental outcomes

Although selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for prenatal depression, there exists controversy over the adverse effects of SSRI use on fetal development. Few studies have adequately isolated outcomes due to SSRI exposure and those due to maternal psychiatric conditions. Here, we directly investigated the outcomes of exposure to widely-used SSRIs fluoxetine and citalopram on the developing nervous system of Xenopus laevis tadpoles, using an integrative experimental approach. We exposed tadpoles to low doses of citalopram and fluoxetine during a critical developmental period and found that the different groups of tadpoles displayed opposing behavioral effects. While both groups showed reduced schooling behavior, the fluoxetine group showed increased seizure susceptibility and reduced startle habituation. In contrast, the citalopram treated tadpoles had decreased seizure susceptibility and increased habituation. Both groups had abnormal dendritic morphology in the optic tectum, a brain area important for all three behaviors tested. Whole-cell electrophysiological recordings of tectal neurons showed no differences in synaptic function across groups; however, tectal cells from fluoxetine-treated tadpoles had decreased voltage gated K+ currents while cells in the citalopram group had increased K+ currents. Both the behavior and electrophysiological findings indicate that cells and circuits in the fluoxetine treated optic tecta are hyperexcitable, while the citalopram group exhibits decreased excitability. Taken all together, these results show that early developmental exposure to SSRIs is sufficient to induce neurodevelopmental effects, however these effects can be complex and vary depending on the SSRI used. This may explain some of the discrepancies across human studies, and further underscores the importance of serotonergic signaling for the developing nervous system.

neuroscience↗