Pelkey Kenneth A, Barksdale Elizabeth, Craig Michael T, Yuan Xiaoqing, Sukumaran Madhav, Vargish Geoffrey A, Mitchell Robert M, Wyeth Megan S, Petralia Ronald S, Chittajallu Ramesh, Karlsson Rose-Marie, Cameron Heather A, Murata Yasunobu, Colonnese Matthew T, Worley Paul F, McBain Chris J
Program in Developmental Neuroscience, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, 35 Lincoln Drive, Bethesda, MD 20892, USA.
Program in Developmental Neuroscience, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, 35 Lincoln Drive, Bethesda, MD 20892, USA.
Neuron. 2015 Mar 18;85(6):1257-72. doi: 10.1016/j.neuron.2015.02.020. Epub 2015 Mar 5.
Circuit computation requires precision in the timing, extent, and synchrony of principal cell (PC) firing that is largely enforced by parvalbumin-expressing, fast-spiking interneurons (PVFSIs). To reliably coordinate network activity, PVFSIs exhibit specialized synaptic and membrane properties that promote efficient afferent recruitment such as expression of high-conductance, rapidly gating, GluA4-containing AMPA receptors (AMPARs). We found that PVFSIs upregulate GluA4 during the second postnatal week coincident with increases in the AMPAR clustering proteins NPTX2 and NPTXR. Moreover, GluA4 is dramatically reduced in NPTX2(-/-)/NPTXR(-/-) mice with consequent reductions in PVFSI AMPAR function. Early postnatal NPTX2(-/-)/NPTXR(-/-) mice exhibit delayed circuit maturation with a prolonged critical period permissive for giant depolarizing potentials. Juvenile NPTX2(-/-)/NPTXR(-/-) mice display reduced feedforward inhibition yielding a circuit deficient in rhythmogenesis and prone to epileptiform discharges. Our findings demonstrate an essential role for NPTXs in controlling network dynamics highlighting potential therapeutic targets for disorders with inhibition/excitation imbalances such as schizophrenia.
回路计算需要主细胞（PC）放电在时间、程度和同步性上的精确性，这在很大程度上由表达小白蛋白的快速发放中间神经元（PVFSIs）来执行。为了可靠地协调网络活动，PVFSIs表现出特殊的突触和膜特性，这些特性促进有效的传入募集，例如高电导、快速门控、含GluA4的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPARs）的表达。我们发现，PVFSIs在出生后第二周上调GluA4，这与AMPAR聚集蛋白NPTX2和NPTXR的增加同时发生。此外，在NPTX2（-/-）/NPTXR（-/-）小鼠中，GluA4显著减少，随之PVFSI的AMPAR功能降低。出生后早期的NPTX2（-/-）/NPTXR（-/-）小鼠表现出回路成熟延迟，具有允许巨大去极化电位的延长的关键期。幼年NPTX2（-/-）/NPTXR（-/-）小鼠显示前馈抑制减少，产生一个缺乏节律发生且易发生癫痫样放电的回路。我们的发现证明了NPTXs在控制网络动态中的重要作用，突出了针对诸如精神分裂症等抑制/兴奋失衡疾病的潜在治疗靶点。
