Department of Biological Sciences, Department of Cell and Developmental Biology, The Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University and Medical Center, Nashville, TN 37235, USA.
Department of Biological Sciences, Department of Cell and Developmental Biology, The Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University and Medical Center, Nashville, TN 37235, USA
Development. 2015 Apr 1;142(7):1346-56. doi: 10.1242/dev.117127.
The activity-dependent refinement of neural circuit connectivity during critical periods of brain development is essential for optimized behavioral performance. We hypothesize that this mechanism is defective in fragile X syndrome (FXS), the leading heritable cause of intellectual disability and autism spectrum disorders. Here, we use optogenetic tools in the Drosophila FXS disease model to test activity-dependent dendritogenesis in two extrinsic neurons of the mushroom body (MB) learning and memory brain center: (1) the input projection neuron (PN) innervating Kenyon cells (KCs) in the MB calyx microglomeruli and (2) the output MVP2 neuron innervated by KCs in the MB peduncle. Both input and output neuron classes exhibit distinctive activity-dependent critical period dendritic remodeling. MVP2 arbors expand in Drosophila mutants null for fragile X mental retardation 1 (dfmr1), as well as following channelrhodopsin-driven depolarization during critical period development, but are reduced by halorhodopsin-driven hyperpolarization. Optogenetic manipulation of PNs causes the opposite outcome--reduced dendritic arbors following channelrhodopsin depolarization and expanded arbors following halorhodopsin hyperpolarization during development. Importantly, activity-dependent dendritogenesis in both neuron classes absolutely requires dfmr1 during one developmental window. These results show that dfmr1 acts in a neuron type-specific activity-dependent manner for sculpting dendritic arbors during early-use, critical period development of learning and memory circuitry in the Drosophila brain.
在大脑发育的关键时期，神经回路连接的活动依赖性细化对于优化行为表现至关重要。我们假设这种机制在脆性 X 综合征（FXS）中存在缺陷，FXS 是遗传性智力障碍和自闭症谱系障碍的主要原因。在这里，我们使用果蝇 FXS 疾病模型中的光遗传学工具来测试两个蘑菇体（MB）学习和记忆脑区的外生神经元中的活动依赖性树突发生：（1） 投射到 MB 花萼微小球内的 Kenyon 细胞（KCs）的输入投射神经元（PN），和（2） 由 KCs 投射到 MB 花梗的输出 MVP2 神经元。输入和输出神经元类都表现出独特的活动依赖性关键期树突重塑。在缺乏脆性 X 智力低下蛋白 1（dfmr1）的果蝇突变体中，以及在关键期发育过程中用光遗传学驱动去极化后，MVP2 树突体扩张，但在 halorhodopsin 驱动的超极化下会减少。对 PN 的光遗传学操作会产生相反的结果——用光遗传学驱动去极化后树突减少，而在发育过程中用光遗传学驱动超极化后树突扩张。重要的是，这两种神经元类的活动依赖性树突发生在一个发育窗口中绝对需要 dfmr1。这些结果表明，dfmr1 在果蝇大脑中学习和记忆回路的早期使用、关键期发育过程中，以神经元类型特异性的活动依赖性方式塑造树突。
