Differential effects mediated by GABA(A) receptors in thalamic nuclei in lh/lh model of absence seizures
Differential effects mediated by GABA(A) receptors in thalamic nuclei in lh/lh model of absence seizures
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DOI：
10.1016/s0920-1211(97)01023-1
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发表时间：
1997-04-01
影响因子：
2.2
通讯作者：
Cao, Z
中科院分区：
文献类型：
--
作者：
Hosford, DA;Wang, Y;Cao, Z
失神癫痫表现为丘脑皮质神经元的同步放电，由丘脑网状核（NRT）的强直性gaba能输出驱动。激活NRT神经元上的GABA(A)受体可减少NRT输出并延缓丘脑皮质的突发放电。虽然NRT中的这一机制可能是苯二氮卓类药物抗失神作用的基础，但它并不能解释巴比妥类药物会加重失神发作的观察结果。在这项研究中，我们验证了氯硝西泮和苯巴比妥对缺失癫痫的lh/lh遗传模型中GABA(A)受体产生不同影响的假设，与VLa（一个包含丘脑皮质神经元的原型传递核）相比，NRT中微量注射氯硝西泮和苯巴比妥对缺失癫痫的影响不同。在NRT中，苯巴比妥（16-1600 nmol/插管）、氯硝西泮（160-2200 pmol/插管）和muscimol （8.8-263 pmol/插管）显著抑制癫痫发作频率。在VLa中，苯巴比妥（1.6 nmol）和muscimol （0.88 pmol）增加了癫痫发作频率，而高剂量（分别为160 nmol和88 pmol）显著抑制了癫痫发作频率。相比之下，氯硝西泮即使在2.2 nmol的剂量下也对癫痫发作频率没有影响；同样的剂量显著抑制NRT微注射后的失神发作。这些发现表明，NRT中GABA(A)受体的激活可能抑制失神发作，而苯巴比妥可能通过作用于丘脑皮质细胞（VLa）中的GABA(A)受体而加重失神发作。区域特异性GABA(A)受体异构体可能是氯硝西泮显微注射到NRT和VLa后的不同效果的基础。(C) 1997爱思唯尔科学有限公司
Absence seizures represent synchronized burst-firing of thalamocortical neurons, which are driven by tonic GABAergic output of nucleus reticularis thalami (NRT). Activation of GABA(A) receptors on NRT neurons reduces NRT output and retards thalamocortical burst-firing. Although this mechanism in NRT may underlie antiabsence effects of benzodiazepines, it does not explain observations that barbiturates can worsen absence-seizures. In this study we tested the hypothesis that clonazepam and phenobarbital produce differential effects on GABA(A) receptors in the lh/lh genetic model of absence seizures after microinjection into NRT compared to VLa, a prototypic relay nucleus containing thalamocortical neurons. In NRT, phenobarbital (16-1600 nmol/cannula), clonazepam (160-2200 pmol/cannula) and muscimol (8.8-263 pmol/cannula) significantly suppressed absence seizure frequency. In VLa, phenobarbital (1.6 nmol) and muscimol (0.88 pmol) increased seizure frequency, whereas higher doses (160 nmol and 88 pmol, respectively) significantly suppressed seizure frequency. In contrast, clonazepam produced no effect on seizure frequency even at a dose of 2.2 nmol; this same dose significantly suppressed absence seizures after microinjection into NRT. These findings suggest that activation of GABA(A) receptors in NRT may suppress absence seizures, and that phenobarbital may worsen absence seizures through actions on GABA(A) receptors in thalamocortical cells (VLa). Region-specific GABA(A) receptor isoforms may underlie the contrasting effects of clonazepam after microinjection into NRT and VLa. (C) 1997 Elsevier Science B.V.