Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA.
The Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, MD 21205, USA.
Cell Rep. 2019 Jan 29;26(5):1089-1097.e3. doi: 10.1016/j.celrep.2019.01.004.
The MEF2 family of transcription factors restricts excitatory synapse number in an activity-dependent fashion during development, yet MEF2 has not been implicated in long-term synaptic depression (LTD), which is thought to initiate synapse elimination. Mutations in MEF2 pathways are implicated in autism spectrum disorders, which include cerebellar dysfunction. Here, we test the hypothesis that cerebellar LTD requires postsynaptic activation of MEF2. Knockdown of MEF2D produces suppression of the transcription-dependent late phase of LTD in cultured Purkinje cells. The late phase of LTD is also completely blocked in Purkinje cells derived from MEF2A+MEF2D null mice and rescued with plasmids that drive expression of MEF2D but not phosphatase-resistant mutant MEF2D S444D. Wild-type Purkinje cells transfected with a constitutively active form of MEF2 show no alterations of synaptic strength. Thus, postsynaptic activation of MEF2 by S444 dephosphorylation is necessary, but not sufficient, for the late phase of cerebellar LTD.
MEF2 转录因子家族在发育过程中以活性依赖的方式限制兴奋性突触的数量，但 MEF2 并未被牵连到长时程突触抑制（ LTD ）中，后者被认为是引发突触消除的原因。MEF2 通路的突变与包括小脑功能障碍在内的自闭症谱系障碍有关。在这里，我们检验了小脑 LTD 需要 MEF2 的突触后激活的假设。MEF2D 的敲低会抑制培养的浦肯野细胞中依赖于转录的 LTD 的晚期阶段。来自 MEF2A+MEF2D 缺失小鼠的浦肯野细胞中，LTD 的晚期阶段也完全被阻断，并且可以通过驱动 MEF2D 表达而不是磷酸酶抗性突变 MEF2D S444D 的质粒进行挽救。转染组成型激活形式的 MEF2 的野生型浦肯野细胞没有改变突触强度。因此，S444 去磷酸化介导的 MEF2 的突触后激活对于小脑 LTD 的晚期阶段是必要的，但不是充分的。
