Apoptotic molecules in synapse plasticity

神经元迁移是中枢神经系统发育的重要过程。神经元迁移后到达内颗粒细胞层，实现终末分化。小脑颗粒细胞迁移行为的位置特异性改变需要脑源性神经营养因子、生长抑素、EphB2受体和离子通道等多分子和信号系统的协同作用。迄今为止，一些报告已经提供了直接的证据，证明离子通道和小脑细胞迁移之间的联系。培养的小脑颗粒细胞具有钾（K+）电流，包括快速瞬态和延迟整流向外电流。小脑颗粒神经元中的K+通道负责决定神经元动作电位频率，控制神经元间突触接触强度，促进神经元静息膜电位，调节单个神经元的兴奋性。我们在早期的研究中发现，低K+介质诱导的小脑颗粒神经元凋亡与电流和振幅的增加有关。褪黑素（MT）可以通过受体或非受体机制调节离子通道，如K+、钙或氯离子，并保护颗粒神经元免受凋亡。MT通过相关的MT受体作为神经调节剂影响许多生理功能。MT水平的改变已经在一些精神和神经疾病中被描述。MT的作用可归因于它与三种受体的相互作用，这三种受体目前已被确定为MT1R、MT2R和MT3R，并以海马、大脑和小脑皮层和视网膜为特征。

Neuronal migration is an essential process in the development of the central nervous system. After migration, neurons arrive at the internal granule cell layer and achieve terminal differentiation. Position-specific changes in migratory behavior of cerebellar granule cells require coordinated activity of multiple molecules and signaling systems, such as brain derived neurotrophic factor, somatostatin, EphB2 receptor, and ion channels. To date, a few reports have provided direct evidence for the link between ion channels and cell migration in the cerebellum. Cerebellar granule cells grown in culture possess potassium (K+) currents which include fast transient and delayed rectifier outward currents. K+ channels in cerebellar granule neurons are responsible for determining the neuronal action potential frequency, controlling the strength of synaptic contacts between neurons, contributing to the neuronal resting membrane potential, and regulating excitability of individual neurons. We showed in an earlier study that apoptosis of cerebellar granule neurons induced in low K+ medium was associated with increased current and amplitudes. Melatonin (MT) can modulate ion channels, such as K+, calcium or chloride, and protect granule neurons against apoptosis by receptor or non-receptor mechanisms. MT influences a number of physiological functions by working as a neuromodulator through associated MT receptors. Alterations of the levels of MT have been described in several psychiatric and neurological disorders. The action of MT can be ascribed to its interaction with three receptors that have now been identified as MT1R, MT2R and MT3R and characterized in the hippocampus, cerebral and cerebellar cortex and retina. In the present study, we examined the effect of MT on granule cell migration. MT increased delayed rectifier outward K+ current amplitude and migration of granule cells, whereas TEA, a K+ channel blocker, decreased the delayed rectifier outward K+ current and slowed migration of the granule cells. Our experiments revealed the existence of TEA-sensitive K+ channel-dependent migration of cerebellar granule cells, and showed that MT stimulates granule cell migration by an increase in K+ channel current, which follows cAMP signal transduction. Although studies on the role of ion channels and ion transporters in cell migration are at an early stage, there is increasing evidence that membrane ion channels are involved in cell locomotion. K+ channels function substantially in the modulation of cell migration suggesting that the activation of K+ channels is responsible for the intracellular K+ loss, which might consequently cause intra-signal transduction leading to cell migration. Incubation of cells with TEA inhibited the K+ outward current and suppressed cell migration, as measured by transwell analysis, and guides the migration of granule cells from the external granule cell layer to the inner granule cell layer in slice cultures. Furthermore, the increasing effect of MT on K+ outward current on cell migration is mediated by MT2R. We found that the reversal effect of TEA on MT-induced migration is incomplete. This reveals, although indirectly, some mechanisms for the facilitory effect of MT on migration other than through modulating the TEA-sensitive K+ channel to promote migration. Among the possible mechanisms underlying the potentiation by MT of K+ currents, cAMP is a major intracellular second messenger that mediates MT regulation of cell functions. In a variety of cells, MT does not alter the basal level of cAMP but inhibits the intracellular accumulation of cAMP. For cyclic nucleotide signaling, cAMP signaling acts as a brake on granule movement. We show that although the application of TEA and cAMP completely block MT-induced K+ current potentiation. MT retains part of the stimulatory effect on cell migration. These data suggest that the MT-induced effect on cerebellar granule cell migration involves an additional signaling pathway associated with MTR. This proposed model illustrates the signaling cascade involved in the neurotrophic action of MT on cerebellar granule cells acting through MT2R, decreases intracellular cAMP and stimulates cell migration.