GABAergic neurons exhibit subtype-specific changes in the developing somatosensory cortex of a rat model of Fragile X Syndrome.

Introduction: GABAergic interneurons (IN) are critical for the precise timing and flow of information in cortical circuits. Loss of GABAergic IN function has been suggested as a potential translationally relevant mechanism of neuropathology in Fragile X Syndrome (FXS). Indeed, in rodent models of FXS, some IN populations may display reduced number, while genes associated with other IN type upregulated. However, it remains unknown how these cell populations, and their cell-type specific gene expression patterns are regulated in early development across other mammalian models of FXS. Methods: Here we utilise an outbred rat model of FXS, in which we have performed single-nucleus RNA sequencing analysis in neonatal development of the somatosensory cortex. We then use immunohistochemistry to measure the number and distribution of neurochemically identified GABAergic IN subtypes from early development until adolescence in the somatosensory cortex. Results: We find that GABAergic INs in a rat model of FXS display clear evidence of transcriptomic alteration compared to wild-type littermates in early brain development. These effects are most profound in putative parvalbumin INs, but with modest changes in other cell types. From immunohistochemistry, we find that parvalbumin INs appear largely unaffected in density in distribution, but we observe a large upregulation in the number of somatostatin-expressing INs. Conclusion: GABAergic INs may display cell-type specific transcriptomic regulation in response to the loss of FMRP. Our data suggests minimal alteration of parvalbumin IN density or distribution, but upregulated somatostatin cell numbers. These data partially agree with previous observations in mouse models of FXS.