Methamphetamine-associated cleavage of the synaptic adhesion molecule intercellular adhesion molecule-5
Methamphetamine-associated cleavage of the synaptic adhesion molecule intercellular adhesion molecule-5
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DOI：
10.1111/j.1471-4159.2010.07153.x
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发表时间：
2011-08-01
影响因子：
4.7
通讯作者：
Lim, Seung T.
中科院分区：
文献类型：
--
作者：
Conant, Katherine;Lonskaya, Irina;Lim, Seung T.
Methamphetamine (MA) is a highly addictive psychostimulant that, used in excess, may be neurotoxic. Although the mechanisms that underlie its addictive potential are not completely understood, in animal models matrix metalloproteinase (MMP) inhibitors can reduce behavioral correlates of addiction. In addition, evidence from genome-wide association studies suggests that polymorphisms in synaptic cell-adhesion molecules (CAMs), known MMP substrates, are linked to addictive potential in humans. In the present study, we examined the ability of MA to stimulate cleavage of intercellular adhesion molecule-5 (ICAM-5), a synaptic CAM expressed on dendritic spines in the telencephalon. Previous studies have shown that shedding of ICAM-5 is associated with maturation of dendritic spines, and that MMP-dependent shedding occurs with long term potentiation. Herein, we show that MA stimulates ecto-domain cleavage of ICAM-5 in vitro, and that this is abrogated by a broad spectrum MMP inhibitor. We also show that an acute dose of MA, administered in vivo, is associated with cleavage of ICAM-5 in murine hippocampus and striatum. This occurs within 6 h and is accompanied by an increase in MMP-9 protein. In related experiments, we examined the potential consequences of ICAM-5 shedding. We demonstrate that the ICAM-5 ectodomain can interact with beta(1) integrins, and that it can stimulate beta(1) integrin-dependent phosphorylation of cofilin, an event that has previously been linked to MMP-dependent spine maturation. Together these data support an emerging appreciation of MMPs as effectors of synaptic plasticity and suggest a mechanism by which MA may influence the same.
