Biology subjects

Derham, A.

Publications and source records attributed to Derham, A..

3 recordsLinked to original sources

bioRxiv2026

Astrocytic FMRP regulates the function of spinal parvalbumin-expressing neurons in Fragile X Syndrome

Tactile hypersensitivity is a common symptom of Fragile X Syndrome (FXS) characterized by over-responsiveness to innocuous touch or textures. Yet, the neural circuitry underlying this altered sensory processing remains incompletely understood. Previous studies have focused on cortical and peripheral neuron dysfunction. However, the spinal dorsal horn circuits, which make up the first central site of somatosensory integration, also comprises elements that could contribute to the hypersensitivity to innocuous stimuli, yet its involvement in this pathology has remained incompletely understood. Here, we show that spinal parvalbumin (PV)-expressing interneurons (PVNs), an inhibitory population that gates touch sensory input from activating nociceptive pathways, are dysfunctional in FXS. Using a mouse model of FXS (global Fmr1 knockout; gKO), we showed that dorsal horn PVNs exhibit impaired function characterized by reduced PV expression and inability to sustain tonic firing. To determine whether these deficits arise through cell-intrinsic mechanisms, we selectively deleted Fmr1 in PVNs. This deletion failed to reproduce the molecular and electrophysiological changes observed in the gKO mice. In contrast, astrocyte-specific deletion of Fmr1 recapitulated key features of the gKO mice, including decreased PV expression and firing. To understand the biophysical basis of this firing deficit, we simulated spinal PVNs using conductance-based Hodgkin-Huxley type modelling. Surprisingly, modifying intrinsic membrane conductances alone was insufficient to account for the experimental data. In fact, PVN firing required incorporation of an additional calcium-dependent extrinsic synaptic component consistent with the experimental finding that astrocytic, but not PVN-specific, loss of FMRP reproduced the PVN phenotype in gKO mice. Together, these findings show that these deficits in spinal PVNs arise primarily from loss of FMRP in astrocytes rather than in PVNs themselves. It reveals astrocyte-dependent dysfunction of dorsal horn inhibitory circuits as a previously uncharacterized consequence of FXS.

neuroscience↗

bioRxiv2024

Deficits in forelimb reach learning in a mouse model of Fragile X syndrome

Fragile X syndrome is a leading cause of intellectual disability and autism spectrum disorder, for which therapies are limited. A mouse model of Fragile X syndrome, the Fmr1 knockout (KO) mouse, has been particularly valuable for interrogating the molecular, cellular, and circuit mechanisms that underlie the neurological deficits seen in this syndrome. Key deficits in Fragile X syndrome include impairments in social behaviors, cognition, and motor learning. Given the difficulties in extrapolating more complex human behaviors to mouse models, simple motor behaviors are a particularly tractable form of learning to study in the mouse. We investigated a form of forelimb reach learning in Fmr1 KO mice, precisely quantifying different parameters of the task using both manual analysis and DeepLabCut-based tracking of reach trajectories. While Fmr1 KO mice show impaired learning overall, our results demonstrated that the presence or absence of a cue that signals reward alleviates some of the deficits. In addition to a single metric of success in learning, we determined the specific parameters of the motor behavior that were responsible for that success or failure. In particular, our results suggested that Fmr1 KO mice showed impaired improvement in the trajectory of the reach, reflected by a greater likelihood of completely missing the target, and in a lower learning index for the optimal reach trajectory. In addition, we fully described the features underlying learning, including categorizing the first attempt during trials, failed reaches where mice make contact with the reward, the number of trials where no attempts were made, as well as how the pattern of these different behaviors varies in Fmr1 KO mice. Our findings provide an essential framework for linking specific behavioral impairments in motor learning to the cellular and circuit mechanisms that support them.

neuroscience↗

bioRxiv2024

Direct lineage conversion of postnatal mouse cortical astrocytes to oligodendrocyte lineage cells

Oligodendrocyte lineage cells (OLCs) are lost in many CNS diseases. Here, we investigate the generation of new OLCs via ectopic expression of Sox10, Olig2 or Nkx6.2 in mouse postnatal astrocytes. Using stringent analyses including, Aldh1l1-astrocyte fate mapping and live cell imaging we confirm that Sox10 and Olig2, but not Nkx6.2, convert Aldh1l1pos astrocytes to induced OLCs (iOLCs). With single cell RNA sequencing (scRNA-seq) we uncover the molecular signatures of iOLCs. Transcriptomic analysis of Sox10- and control cultures over time reveals a clear trajectory from astrocytes to iOLCs. Finally, perturbation models CellOracle and Fatecode support the idea that Sox10 drives cells towards a terminal iOLC fate. Altogether, this multidimensional analysis shows bonafide conversion of astrocytes to iOLCs using Sox10 or Olig2 and provides a foundation for astrocyte DLR strategies to promote OLC repair.

developmental biology↗