Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA.
Neuron. 2021 Apr 21;109(8):1333-1349.e6. doi: 10.1016/j.neuron.2021.03.006. Epub 2021 Mar 25.
To establish functional neural circuits in the brain, synaptic connections are refined by neural activity during development, where active connections are maintained and inactive ones are eliminated. However, the molecular signals that regulate synapse refinement remain to be elucidated. When we inactivate a subset of neurons in the mouse cingulate cortex, their callosal connections are eliminated through activity-dependent competition. Using this system, we identify JAK2 tyrosine kinase as a key regulator of inactive synapse elimination. We show that JAK2 is necessary and sufficient for elimination of inactive connections; JAK2 is activated at inactive synapses in response to signals from other active synapses; STAT1, a substrate of JAK2, mediates inactive synapse elimination; JAK2 signaling is critical for physiological refinement of synapses during normal development; and JAK2 regulates synapse refinement in multiple brain regions. We propose that JAK2 is an activity-dependent switch that serves as a determinant of inactive synapse elimination.
为了在大脑中建立功能性神经回路，突触连接在发育过程中通过神经活动进行精细调整，其中活跃的连接得到维持，而不活跃的连接则被消除。然而，调节突触精细调整的分子信号仍有待阐明。当我们使小鼠扣带皮层中的一小部分神经元失活时，它们的胼胝体连接通过活性依赖的竞争而被消除。利用这个系统，我们确定 JAK2 酪氨酸激酶是不活跃突触消除的关键调节因子。我们表明 JAK2 对于不活跃连接的消除是必要且充分的；JAK2 在对来自其他活跃突触的信号作出反应时被激活于不活跃突触上；STAT1，JAK2 的底物，介导不活跃突触的消除；JAK2 信号对于正常发育过程中突触的生理精细调整至关重要；并且 JAK2 调节多个脑区中的突触精细调整。我们提出 JAK2 是一个活性依赖性开关，作为不活跃突触消除的决定因素。
