Biology subjects

Mery, P.-F.

Publications and source records attributed to Mery, P.-F..

4 recordsLinked to original sources

bioRxiv2024

Functional expression and sex dimorphism of the T-type Cav3.2 Calcium Channel in human DRG Neurons

T-type/Cav3 calcium channels are key in neuronal excitability and pain processing with Cav3.2 being the prominent isoform in primary sensory neurons of the dorsal root ganglion (DRG). Its pharmacological inhibition or gene silencing induces analgesia in several preclinical models of inflammatory and neuropathic pain. However, the presence of Cav3.2, encoded by the CACNA1H gene, in human DRG neurons remains unresolved. Using RNA in-situ hybridization and electrophysiological recordings, we show that human DRGs express Cav3.2 in a subset of neurons positive for the neurotrophic factor receptor TrkB (NTRK2 gene). The Cav3.2 current exhibits typical biophysical and pharmacological properties, including inhibition by a low concentration of nickel and by Z944, a specific T-type calcium channel blocker in advanced clinical development. Conversely, ABT-639, a T-type calcium channel inhibitor that failed in Phase 2 trials for pain relief, does not inhibit Cav3.2 currents in human DRG neurons. Importantly, Cav3.2 currents are prominent in neurons from female organ donors, supporting the presence of sex differences in pain mechanisms in humans. These findings underscore the potential of continued exploration of Cav3.2 as a therapeutic target for pain treatment and highlight a specific subset of human neurons that likely rely on this channel to modulate their excitability.

neuroscience↗

bioRxiv2024

T-type calcium channels participate in intrinsic and synaptic activity of PKCγ neurons of the dorsal horn of the spinal cord during chronic pain

ABSTRACTThe disinhibition of the excitatory PKC{gamma} interneurons plays a central role during mechanical allodynia in the dorsal horn of the spinal cord, routing harmless information to nociceptive pathways. The T-type calcium channel Cav3.2, necessary for mechanical and cold allodynia, is found in most PKC{gamma} neurons of the spinal cord. In this study, the role of Cav3.2 in PKC{gamma} neurons was studied after its pharmacological inhibition and its conditional deletion (KO) in Cav3.2GFP-Flox KI x PKC{gamma}-CreERT2 x Ai14 mice in normal conditions and in the spared-nerve-injury (SNI) model of neuropathic pain. Conditional deletion of Cav3.2 increased the hind-paw basal mechanical sensitivity before surgery, and decreased mechanical pain 7 days, but not 28 days, after surgery. At the cellular level, Cav3.2 participated in the low-threshold currents of PKC{gamma} neurons and the T-type calcium current of PKC{gamma} neurons was decreased in KO mice as compared to wild-type (WT). This loss did not convert into proportional alterations in subthreshold properties including "rebound" potentials, suggesting the involvement of other T-type channels. Action potential kinetics and firing properties seemed similar in WT and KO mice too, but rebound potentials were diminished in the SNI model in WT but not in KO mice. In addition, the modulations of firing properties induced by T-type channel pharmacological blocker Z944 observed in WT mice were absent in KO mice and after SNI. Furthermore, the pairing of action potentials was modified after SNI in WT mice, and not in KO mice. At the synaptic level, excitatory currents were lowered 7- and 28-days after surgery, while inhibitory currents were lowered only at 28 days. These changes were not found in Cav3.2-ablated neurons. Miniature currents analysis indicated that Cav3.2 was involved in both excitatory and inhibitory synaptic transmissions at the level of PKC{gamma} neurons. Surprisingly, Z944 did not mimic the effects of Cav3.2 ablation in PKC{gamma} neurons, suggesting distinct and eventually opposite roles of other T-type calcium channels. Altogether, our results show that Cav3.2 is not mandatory for firing of PKC{gamma} neurons of the dorsal horn of the spinal cord, but that it participates to the SNI-induced changes in their intrinsic and synaptic activity, including changes in their excitatory and inhibitory controls. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=147 SRC="FIGDIR/small/627933v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@1a297daorg.highwire.dtl.DTLVardef@19f7a76org.highwire.dtl.DTLVardef@120f688org.highwire.dtl.DTLVardef@119658e_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

The Human Motoneuron Expression Signature is Defined by ALS-Related Genes

The mammalian spinal cord functions as a community of glial and neuronal cell types to accomplish sensory processing, autonomic control, and movement; conversely, the dysfunction of these cell types following spinal cord injury or disease states can lead to chronic pain, paralysis, and death. While we have made great strides in understanding spinal cellular diversity in animal models, it is crucial to characterize human biology directly to uncover specialized features of basic function and to illuminate human pathology. Here, we present a cellular taxonomy of the adult human spinal cord using single nucleus RNA-sequencing with spatial transcriptomics and antibody validation. We observed 29 glial clusters, including rare cell types such as ependymal cells, and 35 neuronal clusters, which we found are organized principally by anatomical location. To demonstrate the potential of this resource for understanding human disease, we analyzed the transcriptome of spinal motoneurons that are prone to degeneration in amyotrophic lateral sclerosis (ALS) and other diseases. We found that, compared with all other spinal neurons, human motoneurons are defined by genes related to cell size, cytoskeletal structure, and ALS, thereby supporting a model of a specialized motoneuron molecular repertoire that underlies their selective vulnerability to disease. We include a publicly available browsable web resource with this work, in the hope that it will catalyze future discoveries about human spinal cord biology.

neuroscience↗

bioRxiv2021

The impact of C-Tactile Low threshold mechanoreceptors on affective touch and social interactions in mice.

Affective touch is necessary for proper neurodevelopment and sociability. However, it is still unclear how the neurons innervating the skin detect affective and social behaviours. To clarify this matter, we targeted a specific population of somatosensory neurons in mice, named C-low threshold mechanoreceptors (C-LTMRs), that appears particularly well suited physiologically and anatomically to perceive affective and social touch but whose contribution to these processes has not yet been resolved. Our observations revealed that C-LTMRs functional deficiency from birth induced social isolation and reduced tactile interactions in adults. Conversely, transient increase in C-LTMRs excitability in adults using chemogenetics was rewarding, temporally promoted touch seeking behaviours and thus had pro-social effects on group dynamics. This work provides the first empirical evidence that specific peripheral inputs alone can drive complex social behaviour, demonstrating the existence of a specialised neuronal circuit originating from the skin wired to promote interaction with other individuals.

neuroscience↗