Alterations in cortical excitation and inhibition in genetic mouse models of Huntington's disease.
Alterations in cortical excitation and inhibition in genetic mouse models of Huntington's disease.
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DOI：
10.1523/jneurosci.1592-09.2009
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发表时间：
2009-08-19
期刊：
影响因子：
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通讯作者：
Levine MS
中科院分区：
文献类型：
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作者：
Cummings DM;André VM;Uzgil BO;Gee SM;Fisher YE;Cepeda C;Levine MS
在此之前，我们在亨廷顿病（HD）的R6/2小鼠模型的纹状体中发现了自发兴奋性（EPSC）和抑制性（IPSC）突触后电流的进行性改变。来自这些小鼠的中等大小的棘神经元（MSN）显示出较低的EPSC频率，并且细胞群在约40天（明显的行为表型开始的时间点）开始显示出IPSC频率增加。皮质为纹状体提供主要的兴奋性驱动，并在疾病进展期间受到影响。我们研究了自发EPSC和IPSC的体感皮层锥体神经元在层II/III的切片从三个不同的小鼠模型的HD，R6/2，YAC 128和CAG 140敲入。结果显示，行为表型小鼠自发EPSC发生频率较高，诱发EPSC较大，而R6/2小鼠自发IPSC的发生频率在所有模型中均先升高后降低，表现出典型的R6/2显性行为表型。在微型IPSC和诱发IPSC双脉冲比的变化表明GABA释放的可能性改变。此外，在R6/2小鼠中，GABAA受体的阻断在所有年龄的切片和体内癫痫发作中诱导复杂放电。总之，改变兴奋性和抑制性输入锥体神经元在大脑皮层HD似乎是一个普遍的赤字在整个发展的疾病。此外，皮层和纹状体中突触表型之间的差异对于未来治疗方法的发展是重要的，这可能需要在表型发展的早期进行靶向。
Previously, we identified progressive alterations in spontaneous excitatory (EPSCs) and inhibitory (IPSCs) postsynaptic currents in the striatum of the R6/2 mouse model of Huntington’s disease (HD). Medium-sized spiny neurons (MSNs) from these mice displayed a lower frequency of EPSCs and a population of cells exhibited an increased frequency of IPSCs beginning at about 40 days, a time point when the overt behavioral phenotype begins. The cortex provides the major excitatory drive to the striatum and is affected during disease progression. We examined spontaneous EPSCs and IPSCs of somatosensory cortical pyramidal neurons in layers II/III in slices from three different mouse models of HD, the R6/2, the YAC128 and the CAG140 knock-in. Results revealed that spontaneous EPSCs occurred at a higher frequency and evoked EPSCs were larger in behaviorally phenotypic mice while spontaneous IPSCs were initially increased in frequency in all models and subsequently decreased in R6/2 mice after they displayed the typical R6/2 overt behavioral phenotype. Changes in miniature IPSCs and evoked IPSC paired-pulse ratios suggested altered probability of GABA release. Also, in R6/2 mice, blockade of GABAA receptors induced complex discharges in slices and seizures in vivo at all ages. In conclusion, altered excitatory and inhibitory inputs to pyramidal neurons in the cortex in HD appear to be a prevailing deficit throughout the development of the disease. Furthermore, the differences between synaptic phenotypes in cortex and striatum are important for the development of future therapeutic approaches, which may need to be targeted early in the development of the phenotype.