Hewitt Lauren T, Marron Alyssa M, Brager Darrin H
Department of Neuroscience, Institute for Neuroscience, University of Texas at Austin, Austin, Texas, United States.
School of Life Sciences, University of Nevada at Las Vegas, Las Vegas, Nevada, United States.
J Neurophysiol. 2025 May 1;133(5):1558-1571. doi: 10.1152/jn.00510.2024. Epub 2025 Apr 17.
Fragile X syndrome is the most common inherited form of intellectual disability and the leading monogenetic cause of autism. Studies in mouse models of autism spectrum disorders, including the knockout (FX) mouse, suggest that abnormal inhibition in hippocampal circuits contributes to behavioral phenotypes. In FX mice, changes in multiple voltage-gated ion channels occur in excitatory pyramidal neurons of the hippocampus. Whether there are also changes in the intrinsic properties of hippocampal inhibitory interneurons, however, remains largely unknown. We made whole cell current clamp recordings from both fast-spiking (FS) and low threshold spiking (LTS) interneurons in the stratum oriens region of the hippocampus. We found that LTS, but not FS, interneurons in FX mice had lower input resistance and action potential firing compared with the wild type. When we subdivided LTS interneurons into low-threshold high hyperpolarization-activated current () (LTH) and putative oreins-lacunosum moleculare (OLM) cells (Hewitt et al. 9: e14848, 2021), we found that it was the LTH subgroup that had significantly lower input resistance in FX mice. The difference in input resistance between wild-type and FX LTH interneurons was absent in the presence of the h-channel blocker ZD7288, suggesting a greater contribution of in FX LTH interneurons. Voltage clamp recordings found that indeed, was significantly higher in FX LTH interneurons compared with wild type. Our results suggest that altered inhibition in the hippocampus of FX mice may be due in part to changes in the intrinsic excitability of LTH inhibitory interneurons. In this paper, we use physiological and biochemical approaches to investigate the intrinsic excitability of inhibitory interneurons in hippocampal area CA1 of the fragile X mouse. We found that higher lowers the intrinsic excitability of one specific type of interneuron. This study highlights how changes to voltage-gated ion channels in specific neuronal populations may contribute to the altered excitatory/inhibitory balance in fragile X syndrome.
脆性X综合征是最常见的遗传性智力障碍形式，也是自闭症的主要单基因病因。对自闭症谱系障碍小鼠模型（包括敲除（FX）小鼠）的研究表明，海马回路中异常的抑制作用导致了行为表型。在FX小鼠中，海马兴奋性锥体神经元中多种电压门控离子通道发生了变化。然而，海马抑制性中间神经元的内在特性是否也发生了变化，在很大程度上仍然未知。我们对海马齿状回原层区域的快速放电（FS）和低阈值放电（LTS）中间神经元进行了全细胞电流钳记录。我们发现，与野生型相比，FX小鼠中的LTS中间神经元而非FS中间神经元具有更低的输入电阻和动作电位发放。当我们将LTS中间神经元细分为低阈值高超极化激活电流（）（LTH）和假定的篮状细胞-分子层（OLM）细胞（休伊特等人，9:e14848，2021）时，我们发现正是LTH亚组在FX小鼠中具有显著更低的输入电阻。在存在h通道阻滞剂ZD7288的情况下，野生型和FX LTH中间神经元之间的输入电阻差异消失，这表明在FX LTH中间神经元中作用更大。电压钳记录发现，实际上，与野生型相比，FX LTH中间神经元中的显著更高。我们的结果表明，FX小鼠海马中抑制作用的改变可能部分归因于LTH抑制性中间神经元内在兴奋性的变化。在本文中，我们使用生理和生化方法来研究脆性X小鼠海马CA1区抑制性中间神经元的内在兴奋性。我们发现更高的会降低一种特定类型中间神经元的内在兴奋性。这项研究突出了特定神经元群体中电压门控离子通道的变化如何可能导致脆性X综合征中兴奋性/抑制性平衡的改变。
