Jorge García‐Piqueras

Recent studies have shown that murine and avian Meissner‐like corpuscles are innervated by two distinct mechanoreceptor afferents with different functional properties. In addition, there is evidence that one subpopulation of Meissner corpuscles of monkeys is doubly innervated by mechanoreceptors and nociceptors. In humans, however, most Meissner corpuscles are supplied by a single axon. In the present study, different techniques were used (silver impregnation, immunohistochemistry for axon markers, axonal 3D reconstruction, and double immunofluorescence associated with confocal laser microscopy) to analyze whether human digital Meissner's corpuscles have double innervation. The percentage of Meissner corpuscles with apparent double innervation was minimal, about 2%, but these data were not confirmed when sections processed for double immunofluorescence for peripherin plus neurofilament proteins or TrkB plus Ret were analyzed. In fact, TrkB co‐localized with Ret in the axon of Meissner's corpuscles. In the 3D axonal reconstructions, there was no evidence of double innervation but the single axon had different calibers along its path and very fine collateral protrusions. The present results demonstrate that most human digital Meissner's corpuscles (around 95–98%) are innervated by a single axon in which TrkB and Ret co‐localize, instead of being supplied by two independent TrkB‐ and Ret‐positive axons as occurs in other species.

Schizophrenia is associated with impaired inhibitory neurotransmission and disrupted synaptic plasticity in the medial prefrontal cortex (mPFC), yet the biological mechanisms underlying these deficits may differ between sexes. Here, we used a double-hit rat model, combining perinatal NMDA receptor blockade and post-weaning social isolation, to dissect sex-specific alterations in inhibitory circuit maturation, synaptic plasticity, and prefrontal function. Male double-hit rats exhibited robust schizophrenia-like behaviors, reduced parvalbumin (PV), OTX2, and perineuronal net (PNN) expression, decreased GAD67 levels, and increased DNA damage in PV interneurons, together indicating impaired inhibitory maturation and weakened plasticity. In contrast, females showed milder behavioral deficits but displayed increased PV and OTX2 intensities, enhanced cFos activation in excitatory neurons, and transcriptomic upregulation of glutamatergic, GABAergic, and synapse assembly pathways, suggesting a state of heightened or dysregulated plasticity. Despite these divergent molecular trajectories, in vivo electrophysiology revealed a shared functional endpoint in both sexes: a shift from paired-pulse inhibition to facilitation during basolateral amygdala-evoked responses, reflecting impaired GABAB-mediated inhibitory feedback. Pharmacological blockade of GABAB, but not GABAA, receptors reproduced this phenotype, identifying GABAB signaling as a key mechanism underlying cortical disinhibition. Altogether, our findings reveal that males and females reach convergent prefrontal inhibitory deficits through sex-specific molecular pathways, underscoring the importance of sex as a biological variable in the pathophysiology and treatment of schizophrenia.

Krause’s corpuscles are typical of cutaneous mucous epithelia, like the lip vermillion or the glans clitoridis, and are associated with rapidly adapting low-threshold mechanoreceptors involved in gentle touch or vibration. PIEZO1 and PIEZO2 are transmembrane mechano-gated proteins that form a part of the cationic ion channels required for mechanosensitivity in mammalian cells. They are involved in somatosensitivity, especially in the different qualities of touch, but also in pain and proprioception. In the present study, immunohistochemistry and immunofluorescence were used to analyze the occurrence and cellular location of PIEZO1 and PIEZO2 in human clitoral Krause’s corpuscles. Both PIEZO1 and PIEZO2 were detected in Krause’s corpuscles in both the axon and the terminal glial cells. The presence of PIEZOs in the terminal glial cells of Kraus’s corpuscles is reported here for the first time. Based on the distribution of PIEZO1 and PIEZO2, it may be assumed they could be involved in mechanical stimuli, sexual behavior, and sexual pleasure.

Inherited retinal diseases (IRDs) are a group of diseases whose common landmark is progressive photoreceptor loss. The development of gene‐specific therapies for IRDs is hampered by their wide genetic heterogeneity. Mitochondrial dysfunction is proving to constitute one of the key pathogenic events in IRDs; hence, approaches that enhance mitochondrial activities have a promising therapeutic potential for these conditions. We previously reported that miR‐181a/b downregulation boosts mitochondrial turnover in models of primary retinal mitochondrial diseases. Here, we show that miR‐181a/b silencing has a beneficial effect also in IRDs. In particular, the injection in the subretinal space of an adeno‐associated viral vector (AAV) that harbors a miR‐181a/b inhibitor (sponge) sequence (AAV2/8‐GFP‐Sponge‐miR‐181a/b) improves retinal morphology and visual function both in models of autosomal dominant (RHO‐P347S) and of autosomal recessive (rd10) retinitis pigmentosa. Moreover, we demonstrate that miR‐181a/b downregulation modulates the level of the mitochondrial fission‐related protein Drp1 and rescues the mitochondrial fragmentation in RHO‐P347S photoreceptors. Overall, these data support the potential use of miR‐181a/b downregulation as an innovative mutation‐independent therapeutic strategy for IRDs, which can be effective both to delay disease progression and to aid gene‐specific therapeutic approaches.

The human palmar aponeurosis is involved in hand proprioception, and it contains different sensory corpuscle morphotypes that serve this role. In palmar fibromatosis (classically referred to as Dupuytren's disease), the palmar aponeurosis undergoes fibrous structural changes that, presumably, also affect the nervous system, causing altered perception. We analysed the various sensory nerve formation morphotypes in the palmar aponeuroses of healthy subjects and patients with palmar fibromatosis. To do this, we used immunohistochemistry for corpuscular constituents and the putative mechanoproteins PIEZO2 and acid-sensing ion channel 2. Free nerve endings and Golgi-Mazzoni, Ruffini, paciniform and Pacinian corpuscles were identified in both the healthy and the pathological conditions. The densities of the free nerve endings and Golgi-Mazzoni corpuscles were slightly increased in the pathological tissues. Furthermore, the Pacinian corpuscles were enlarged and displayed an altered shape. Finally, there was also morphological and immunohistochemical evidence of occasional denervation of the Pacinian corpuscles, although no increase in their number was observed. Both PIEZO2 and acid-sensing ion channel 2 were absent from the altered corpuscles. These results indicate that the human palmar aponeurosis is richly innervated, and the free nerve endings and sensory corpuscles within the palmar aponeurosis undergo quantitative and qualitative changes in patients with palmar fibromatosis, which may explain the sensory alterations occasionally reported for this pathology.

Distal diabetic sensorimotor polyneuropathy (DDSP) is the most prevalent form of diabetic neuropathy, and some of the patients develop gradual pain. Specialized sensory structures present in the skin encode different modalities of somatosensitivity such as temperature, touch, and pain. The cutaneous sensory structures responsible for the qualities of mechanosensitivity (fine touch, vibration) are collectively known as cutaneous mechanoreceptors (Meissner corpuscles, Pacinian corpuscles, and Merkel cell–axonal complexes), which results are altered during diabetes. Here, we used immunohistochemistry to analyze the density, localization within the dermis, arrangement of corpuscular components (axons and Schwann-like cells), and expression of putative mechanoproteins (PIEZO2, ASIC2, and TRPV4) in cutaneous mechanoreceptors of subjects suffering clinically diagnosed non-painful and painful distal diabetic sensorimotor polyneuropathy. The number of Meissner corpuscles, Pacinian corpuscles, and Merkel cells was found to be severely decreased in the non-painful presentation of the disease, and almost disappeared in the painful presentation. Furthermore, there was a marked reduction in the expression of axonal and Schwann-like cell markers (with are characteristics of corpuscular denervation) as well as of all investigated mechanoproteins in the non-painful distal diabetic sensorimotor polyneuropathy, and these were absent in the painful form. Taken together, these alterations might explain, at least partly, the impairment of mechanosensitivity system associated with distal diabetic sensorimotor polyneuropathy. Furthermore, our results support that an increasing severity of DDSP may increase the risk of developing painful neuropathic symptoms. However, why the absence of cutaneous mechanoreceptors is associated with pain remains to be elucidated.

The vertebrate skin contains sensory corpuscles that are receptors for different qualities of mechanosensitivity like light brush, touch, pressure, stretch or vibration. These specialized sensory organs are linked anatomically and functionally to mechanosensory neurons, which function as low-threshold mechanoreceptors connected to peripheral skin through Aβ nerve fibers. Furthermore, low-threshold mechanoreceptors associated with Aδ and C nerve fibers have been identified in hairy skin. The process of mechanotransduction requires the conversion of a mechanical stimulus into electrical signals (action potentials) through the activation of mechanosensible ion channels present both in the axon and the periaxonal cells of sensory corpuscles (i.e., Schwann-, endoneurial- and perineurial-related cells). Most of those putative ion channels belong to the degenerin/epithelial sodium channel (especially the family of acid-sensing ion channels), the transient receptor potential channel superfamilies, and the Piezo family. This review updates the current data about the occurrence and distribution of putative mechanosensitive ion channels in cutaneous mechanoreceptors including primary sensory neurons and sensory corpuscles.

Meissner corpuscles are cutaneous mechanoreceptors that are usually located in the dermal papillae of human glabrous skin. Structurally, these sensory corpuscles consist of a mechanoreceptive sensory neuron surrounded by non‐myelinating lamellar Schwann‐like cells. Some authors have described a partially developed fibroblastic capsule of endoneurial or perineurial origin around Meissner corpuscles; however, others have noted that these structures are non‐encapsulated. As there is continuity between the periaxonic cells forming the sensory corpuscles and the cells of the nerve trunks, we used immunohistochemistry to examine the expression of endoneurial (CD34 antigen) or perineurial [Glucose transporter 1 (Glut1)] markers in human cutaneous Meissner corpuscles. We also investigated the immunohistochemical patterns of nestin and vimentin (the main intermediate filaments of the cytoskeleton of endoneurial and perineurial cells, respectively) in Meissner corpuscles. The most important finding from this study was that CD34‐positive cells formed a partial/complete capsule of endoneurial origin around most Meissner corpuscles, without signs of other perineurial Glut1‐positive elements. However, the cytoskeletal proteins of the capsular CD34‐positive cells did not include either nestin or vimentin, so the cytoskeletal composition of these cells remains to be established. Finally, the intensity of the immunoreactivity for CD34 in the capsule decreased with ageing, sometimes becoming completely absent in the oldest individuals. In conclusion, we report the first immunohistochemical evidence of the capsule of Meissner corpuscles in humans and demonstrate the endoneurial origin of the capsule.