Nadif Kasri Nael, Nakano-Kobayashi Akiko, Malinow Roberto, Li Bo, Van Aelst Linda
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Genes Dev. 2009 Jun 1;23(11):1289-302. doi: 10.1101/gad.1783809.
Oligophrenin-1 (OPHN1) encodes a Rho-GTPase-activating protein (Rho-GAP) whose loss of function has been associated with X-linked mental retardation (MR). The pathophysiological role of OPHN1, however, remains poorly understood. Here we show that OPHN1 through its Rho-GAP activity plays a critical role in the activity-dependent maturation and plasticity of excitatory synapses by controlling their structural and functional stability. Synaptic activity through NMDA receptor activation drives OPHN1 into dendritic spines, where it forms a complex with AMPA receptors, and selectively enhances AMPA-receptor-mediated synaptic transmission and spine size by stabilizing synaptic AMPA receptors. Consequently, decreased or defective OPHN1 signaling prevents glutamatergic synapse maturation and causes loss of synaptic structure, function, and plasticity. These results imply that normal activity-driven glutamatergic synapse development is impaired by perturbation of OPHN1 function. Thus, our findings link genetic deficits in OPHN1 to glutamatergic dysfunction and suggest that defects in early circuitry development are an important contributory factor to this form of MR.
少突脑苷脂-1（OPHN1）编码一种Rho鸟苷三磷酸酶激活蛋白（Rho-GAP），其功能丧失与X连锁智力障碍（MR）相关。然而，OPHN1的病理生理作用仍知之甚少。在此我们表明，OPHN1通过其Rho-GAP活性，通过控制兴奋性突触的结构和功能稳定性，在其活性依赖的成熟和可塑性中发挥关键作用。通过NMDA受体激活的突触活动将OPHN1驱动到树突棘中，在那里它与AMPA受体形成复合物，并通过稳定突触AMPA受体选择性增强AMPA受体介导的突触传递和棘突大小。因此，OPHN1信号减少或缺陷会阻止谷氨酸能突触成熟，并导致突触结构、功能和可塑性丧失。这些结果表明，正常的活动驱动的谷氨酸能突触发育因OPHN1功能的扰动而受损。因此，我们的发现将OPHN1的基因缺陷与谷氨酸能功能障碍联系起来，并表明早期神经回路发育缺陷是这种形式的MR的一个重要促成因素。
