Polysialylated NCAM and EphrinA/EphA Regulate Synaptic Development of GABAergic Interneurons in Prefrontal Cortex
Polysialylated NCAM and EphrinA/EphA Regulate Synaptic Development of GABAergic Interneurons in Prefrontal Cortex
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DOI：
10.1093/cercor/bhr392
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发表时间：
2013-01-01
期刊：
影响因子：
3.7
通讯作者：
Maness, Patricia F.
中科院分区：
文献类型：
--
作者：
Brennaman, Leann H.;Zhang, Xuying;Maness, Patricia F.
神经细胞粘附分子（NCAM）在ephrinA/EphA介导的排斥反应中的一种新功能被鉴定为小鼠前额叶皮层GABA能抑制性突触连接发展的重要调节机制。缺失NCAM，EphA 3，或ephrinA 2/3/5的无效突变小鼠增加GABA能篮状中间神经元和锥体细胞之间的发育扣带皮层（层II/III）的体周突触的数量和大小。NCAM损失的一个功能性后果是NCAM无效扣带皮层中微型抑制性突触后电流的幅度增加和动力学加快。NCAM和EphA 3形成了一个分子复合物，并与抑制性突触前标记物囊泡GABA转运体（VGAT）共定位在体周点和扣带皮层的神经元。EphrinA 5治疗促进了皮质切片培养物中增强的绿色荧光蛋白标记的篮状中间神经元的轴突重塑，并诱导了野生型但非NCAM无效突变神经元的生长锥塌陷。需要用聚唾液酸（PSA）修饰的NCAM来促进皮质切片中ephrinA 5诱导的篮状中间神经元的轴突重塑，这可能是通过为ephrinA 5/EphA 3信号传导提供允许的环境。这些结果揭示了一种新的机制，其中NCAM和ephrinAs/EphA 3协调约束GABA能神经元间的树枝状和体周神经支配，可能有助于前额叶皮层电路的兴奋/抑制平衡。
A novel function for the neural cell adhesion molecule (NCAM) was identified in ephrinA/EphA-mediated repulsion as an important regulatory mechanism for development of GABAergic inhibitory synaptic connections in mouse prefrontal cortex. Deletion of NCAM, EphA3, or ephrinA2/3/5 in null mutant mice increased the numbers and size of perisomatic synapses between GABAergic basket interneurons and pyramidal cells in the developing cingulate cortex (layers II/III). A functional consequence of NCAM loss was increased amplitudes and faster kinetics of miniature inhibitory postsynaptic currents in NCAM null cingulate cortex. NCAM and EphA3 formed a molecular complex and colocalized with the inhibitory presynaptic marker vesicular GABA transporter (VGAT) in perisomatic puncta and neuropil in the cingulate cortex. EphrinA5 treatment promoted axon remodeling of enhanced green fluorescent protein-labeled basket interneurons in cortical slice cultures and induced growth cone collapse in wild-type but not NCAM null mutant neurons. NCAM modified with polysialic acid (PSA) was required to promote ephrinA5-induced axon remodeling of basket interneurons in cortical slices, likely by providing a permissive environment for ephrinA5/EphA3 signaling. These results reveal a new mechanism in which NCAM and ephrinAs/EphA3 coordinate to constrain GABAergic interneuronal arborization and perisomatic innervation, potentially contributing to excitatory/inhibitory balance in prefrontal cortical circuitry.