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Experimental Dermatology 2004: 13: 2–4 Blackwell Munksgaard . Printed in Denmark

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Blackwell Munksgaard 2004

EXPERIMENTAL DERMATOLOGY ISSN 0906-6705

Letter to the Editors

Connections between nerve endings and epidermal cells: are they synapses? Chateau Y, Misery L. Connections between nerve endings and epidermal cells: are they synapses? Exp Dermatol 2004: 13: 2–4. # Blackwell Munksgaard, 2004 Abstract: Based on electron microscopy and confocal scanning microscopy, contacts between sensory axons and the cells of the epidermis have been described: with keratinocytes, Langerhans cells, melanocytes and Merkel cells. We would like to initiate a debate on this question: ‘‘Are neuro-epidermal connections synapses?’’. Anatomically, neuro-epidermal junctions can be considered as synapses in our opinion. If neuroepidermal junctions are synapses, they probably belong to the family of en passant synapses, with nerve endings passing along epidermal cells and occasionally connecting to them. In conclusion, we suggest that neuroepidermal junctions could be considered as true synapses, but this does not exclude non synaptic interactions.

Yannick Chateau and Laurent Misery Laboratory of Cutaneous Neurobiology, Department of Dermatology, University Hospital, Brest, France Key words: epidermis – nerve endings – synapse Laurent Misery Laboratory of Cutaneous Neurobiology Department of Dermatology University Hospital Brest, France Tel.: þ33 298 22 35 27 Fax: þ33 298 22 33 82 e-mail: [email protected] Accepted for publication 30 July 2003

Skin (more precisely epidermis) and the nervous system share a common embryonic origin, which is ectodermis. Later in their lifetime, they are clearly differentiated. Skin innervation, however, is very dense. By using new markers (notably PGP 9.5) and immunohistochemistry, numerous free nerve endings have recently been observed in the epidermis (1,2). Based on electron microscopy and confocal scanning microscopy (CSLM), contacts between sensory axons and the cells of the epidermis have been described with keratinocytes (3), Langerhans’ cells (4,5), melanocytes (6), and Merkel cells (7). The existence of synapses between nerve endings and neuro-endocrine cells, such as Merkel cells, is not surprising and they were reported very early. The presence of connections between nerve endings and Langerhans’ cells (4,5), keratinocytes (3), or melanocytes (6) was unexpected. CSLM studies have shown intimate contacts. These contacts can be induced in vitro (Fig. 1). Electron microscopy has shown the presence of numerous unmyelinated axons among epidermal cells with invaginations in epidermal cell bodies, containing many mitochondria, rough endoplasmic reticulum and clear and dense-cored vesicles. The adjacent plasma membranes of melanocytes, Langerhans’ cells, or keratinocytes were slightly thickened, closely

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resembling post-synaptic membrane specializations in nervous tissues. This ultrastructural organization seems to be devoted to the efferent way (8). Moreover, similar connections have been observed in dermis or immune organs (9). In the dermis, connections of nerve endings with both mast cells (10) and dermal dendrocytes (11) have been observed. Skin is innervated primarily by sensory nerves and by postganglionic parasympathetic and sympathetic nerves. Sensory nerves have been shown to function not only as an afferent system which conducts stimuli from the skin to the central nervous system (CNS), but also as an efferent system which stimulates target tissue by secreting several kinds of neurotransmitters in healthy skin or in dermatoses (9). Hence, released neurotransmitters are able to modulate most cutaneous functions, especially the immune skin function, through their binding to specific receptors on the cell membrane of skin cells. Our purpose was not to discuss these data on the neuro-endocrinoimmuno-cutaneous system. All the authors who have observed these connections, including us, have not dared to use the word ‘synapse’. About 106 years after the definition of the synapse by C.S. Sherrington (12), we initiate a debate on this question: ‘Are neuro-epidermal connections synapses?’

Epidermal synapses

Figure 1. Connection between nerve endings and keratinocytes in culture (confocal scanning microscopy).

Nowadays, the most common definition of the synapse is ‘specialized contact zone between two excitable cells’ (12,13). But there is a wide diversity of synapses (12). Palade & Palay were the first to depict synapses under an electron microscope. They found local thickenings of the pre- and post-synaptic membranes, a collection of small vesicles near the pre-synaptic thickening, and an extracellular gap between the two membranes, the synaptic cleft (12). Chemical transmitters bridge this gap by diffusing from release sites on the pre-synaptic side to receptors on the post-synaptic side. A variety of organites are present at the synapse, allowing unambiguous identification of the pre- and post-synaptic structures. Within the pre-synaptic axonal button, clouds of synaptic vesicles are prominent; mitochondria are numerous, as well as tubules of endoplasmic reticulum. A characteristic feature of the synapse is the accumulation of opaque material on the cytoplasmic membrane facing the post-synaptic membrane. This material is identified as neurotransmitter receptors and signaling proteins essential for chemical synaptic transmission (8). Anatomically, neuro-epidermal junctions can be considered as synapses in our opinion.

Structural and functional classifications of axons, dendrites and their synapses are still emerging, owing to the use of electrophysiology, laser scanning, and serial electron microscopy, together with 3D computer-aided reconstruction. The definition of the synapse was initially based on studies on the neuromuscular junction (NMJ) (8,12), describing a nerve ending affixed on the membrane of muscular cell. But synapses in the CNS are mostly en passant. They do not look like the archetype of the synaptic button from the NMJ but rather as an axon passing along a part of another neurone. Hence, if neuro-epidermal junctions are synapses, they probably belong to this kind of synapses, with nerve endings passing along epidermal cells and occasionally connecting to them. Another resemblance with CNS synapses is the reciprocal exchange of information (9,14,15). Indeed, neurones are able to produce neurotransmitters and neuronal growth factors, which induce many effects on skin cells. But skin cells, especially immune cells, are able to produce cytokines, neuronal growth factors, and neurotransmitters, modulating neuronal functions. Recently, heatsensitive transient receptor potential channel expression has been described in keratinocytes (16), indicating that these cells could detect heat similar to neurones. If this is the case, the heat information must somehow be transferred to neurones. Another way to classify synapses is to separate electrical and chemical synapses. In the epidermis, the presence of chemical synapses is obvious, as neurotransmitters are vectors of communication between neurones and skin cells (9,14,15), but there is no evidence showing the existence of electrical synapses. Gap junctions, which are intercellular channels crossing the intermembrane space, are numerous in the epidermis (17), but their presence has not been demonstrated in connections between nerve endings and epidermal cells until now. On the other hand, actions of neurotransmitters are slow in the skin, and some authors suggest that these kinds of slow effects are related to non-synaptic interactions (12,18). Are interactions between skin and the nervous system both synaptic and non-synaptic? We suggest that neuroepidermal junctions could be considered as true synapses, but this does not exclude non-synaptic interactions.

References 1. Kennedy W R, Wendelschafer-Crabb G. The innervation of human epidermis. Neurol Sci 1993: 115: 184–190.

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