Abstract
Lithium chloride has been widely used as a therapeutic mood stabilizer. Although cumulative evidence suggests that lithium plays modulatory effects on postsynaptic receptors, the underlying mechanism by which lithium regulates synaptic transmission has not been fully elucidated. In this work, by using the advantageous neuromuscular synapse, we evaluated the effect of lithium on the stability of postsynaptic nicotinic acetylcholine receptors (nAChRs) in vivo. We found that in normally innervated neuromuscular synapses, lithium chloride significantly decreased the turnover of nAChRs by reducing their internalization. A similar response was observed in CHO-K1/A5 cells expressing the adult muscle-type nAChRs. Strikingly, in denervated neuromuscular synapses, lithium led to enhanced nAChR turnover and density by increasing the incorporation of new nAChRs. Lithium also potentiated the formation of unstable nAChR clusters in non-synaptic regions of denervated muscle fibres. We found that denervation-dependent re-expression of the foetal nAChR γ-subunit was not altered by lithium. However, while denervation inhibits the distribution of β-catenin within endplates, lithium-treated fibres retain β-catenin staining in specific foci of the synaptic region. Collectively, our data reveal that lithium treatment differentially affects the stability of postsynaptic receptors in normal and denervated neuromuscular synapses in vivo, thus providing novel insights into the regulatory effects of lithium on synaptic organization and extending its potential therapeutic use in conditions affecting the peripheral nervous system.
Highlights
Lithium chloride has been widely used as a therapeutic mood stabilizer
Our observations suggest that the incorporation of new nicotinic acetylcholine receptors (nAChRs) is not homogeneous in the plane of the endplate, as it becomes more evident towards the periphery at longer time intervals of nAChR turnover (Fig. 1B)
To analyse the potential effects of lithium on surface nAChR stability, we have set up in vivo assays in the neuromuscular junction (NMJ) of the cranial Levator auris longus (LAL) muscle, a flat, thin, and superficially exposed muscle that facilitates repeated in vivo visualization and m anipulation[38,48,49,50,51]
Summary
Lithium chloride has been widely used as a therapeutic mood stabilizer. cumulative evidence suggests that lithium plays modulatory effects on postsynaptic receptors, the underlying mechanism by which lithium regulates synaptic transmission has not been fully elucidated. Our data reveal that lithium treatment differentially affects the stability of postsynaptic receptors in normal and denervated neuromuscular synapses in vivo, providing novel insights into the regulatory effects of lithium on synaptic organization and extending its potential therapeutic use in conditions affecting the peripheral nervous system. In different synapses, lithium acts through inhibition of the glycogen synthase kinase-3β (GSK3β)[8,9], up-regulation of neurotrophins and their r eceptors[10], and reduction of the AMPA glutamate receptor levels in the cell s urface[9,11,12,13,14] In this regard, even though most of the molecular mechanisms described for lithium effects involve the a ctivity[13] and expression levels[15] of postsynaptic receptors, the ability of lithium to regulate their stability has not been elucidated[13]. Our findings reveal that lithium directly targets postsynaptic nAChR turnover at the NMJ and control their availability in synaptic and non-synaptic regions of normal and injured synapses
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