Increased GABA transmission to GnRH neurons after intrahippocampal kainic acid injection in mice is sex-specific and associated with estrous cycle disruption.
Increased GABA transmission to GnRH neurons after intrahippocampal kainic acid injection in mice is sex-specific and associated with estrous cycle disruption.
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DOI：
10.1016/j.nbd.2022.105822
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发表时间：
2022-10-01
影响因子：
6.1
通讯作者：
Christian-Hinman, CatherineA.
中科院分区：
文献类型：
--
作者：
Ingram, Robbie J.;Leverton, Leanna K.;Daniels, Victoria C.;Li, Jiang;Christian-Hinman, CatherineA.
癫痫患者出现生殖内分泌合并症的几率高于一般人群。临床研究已发现两性患者的黄体生成素 (LH) 释放模式被破坏，这表明下丘脑促性腺激素释放激素 (GnRH) 神经元功能可能发生与癫痫相关的变化。在之前的工作中，我们发现在颞叶癫痫的海马内红藻氨酸 (IHKA) 小鼠模型中，绝情雌性和雄性 GnRH 神经元放电增加。值得注意的是，GABAA 受体激活在成年 GnRH 神经元中具有去极化作用。因此，在这里我们测试了以下假设：IHKA 小鼠中 GnRH 神经元放电的增加与 GnRH 神经元的 GABA 驱动的增加有关。当阻断离子型谷氨酸受体 (iGluR) 以分离 GABA 能突触后电流 (PSC) 时，对照和 IHKA 绝情雌性的 GnRH 神经元之间没有观察到 PSC 频率的差异。然而，在没有 iGluR 阻断的情况下，发情周期中断的 IHKA 雌性的 GnRH 神经元中 GABA PSC 频率增加，但注射生理盐水的对照组和没有动情周期中断的 IHKA 雌性的 GABA PSC 频率没有增加。在动情周期中断的 IHKA 女性中，GABA PSC 振幅也增加。这些发现表明，对于伴有共病周期破坏的 IHKA 女性，GnRH 神经元的前馈 GABA 能传递存在 iGluR 依赖性增加。在男性中，GABA PSC 频率和幅度未改变，但 PSC 持续时间减少。总之，这些发现表明，GABA 传输的增加有助于推动 IHKA 雌性在发情间期的放电增加，并表明 IHKA 小鼠生殖内分泌功能障碍背后存在性别特异性下丘脑机制。
Patients with epilepsy develop reproductive endocrine comorbidities at a rate higher than that of the general population. Clinical studies have identified disrupted luteinizing hormone (LH) release patterns in patients of both sexes, suggesting potential epilepsy-associated changes in hypothalamic gonadotropin-releasing hormone (GnRH) neuron function. In previous work, we found that GnRH neuron firing is increased in diestrous females and males in the intrahippocampal kainic acid (IHKA) mouse model of temporal lobe epilepsy. Notably, GABAA receptor activation is depolarizing in adult GnRH neurons. Therefore, here we tested the hypothesis that increased GnRH neuron firing in IHKA mice is associated with increased GABAergic drive to GnRH neurons. When ionotropic glutamate receptors (iGluRs) were blocked to isolate GABAergic postsynaptic currents (PSCs), no differences in PSC frequency were seen between GnRH neurons from control and IHKA diestrous females. In the absence of iGluR blockade, however, GABA PSC frequency was increased in GnRH neurons from IHKA females with disrupted estrous cycles, but not saline-injected controls nor IHKA females without estrous cycle disruption. GABA PSC amplitude was also increased in IHKA females with disrupted estrous cycles. These findings suggest the presence of an iGluR-dependent increase in feed-forward GABAergic transmission to GnRH neurons specific to IHKA females with comorbid cycle disruption. In males, GABA PSC frequency and amplitude were unchanged but PSC duration was reduced. Together, these findings suggest that increased GABA transmission helps drive elevated firing in IHKA females on diestrus and indicate the presence of a sex-specific hypothalamic mechanism underlying reproductive endocrine dysfunction in IHKA mice.
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影响因子：
3.4
作者：
Adams C;Chen X;Moenter SM
通讯作者：
Moenter SM
影响因子：
5.3
作者：
Christian, Catherine A.;Moenter, Suzanne M.
通讯作者：
Moenter, Suzanne M.
影响因子：
56.9
作者：
BELCHETZ, PE;PLANT, TM;KNOBIL, E
通讯作者：
KNOBIL, E
影响因子：
4.8
作者：
Christian, Catherine A.;Moenter, Suzanne M.
通讯作者：
Moenter, Suzanne M.
影响因子：
2.2
作者：
Bauer, J;Jarre, A;Elger, CE
通讯作者：
Elger, CE