Ordemann Gregory J, Lyuboslavsky Polina, Kizimenko Alena, Brumback Audrey C
Department of Neurology, Dell Medical School at The University of Texas at Austin, Austin, Texas, USA.
Center for Learning and Memory at The University of Texas at Austin, Austin, Texas, USA.
Exp Physiol. 2025 Sep 4. doi: 10.1113/EP092894.
The neurodevelopmental disorder fragile X syndrome (FXS) results from hypermethylation of the FMR1 gene, which prevents production of the FMRP protein. FMRP modulates the expression and function of a variety of proteins, including voltage-gated ion channels, such as hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels, which are integral to rhythmic activity in thalamic structures. Thalamocortical pathology, particularly involving the mediodorsal thalamus (MD), has been implicated in neurodevelopmental disorders such as FXS. MD connectivity with the medial prefrontal cortex (mPFC) is integral to executive functions such as working memory and social behaviours that are disrupted in FXS. We used a combination of retrograde labelling and ex vivo brain slice whole-cell electrophysiology in 40 wild-type and 42 Fmr1 knockout male mice to investigate how a lack of Fmr1 affects intrinsic cellular properties in lateral (MD-L) and medial (MD-M) MD neurons that project to the mPFC (MD→mPFC neurons). In MD-L neurons, Fmr1 knockout decreased the HCN-mediated membrane properties voltage sag and membrane after-hyperpolarization. We also identified a delay in rebound spike timing in both complex bursts and low-threshold spikes. In Fmr1 knockout mice, reduced HCN channel activity in MD-L→mPFC neurons impaired both the timing and the magnitude of HCN-mediated membrane potential regulation. Changes in response timing might adversely affect rhythm propagation in Fmr1 KO thalamocortical circuitry. MD thalamic neurons are crucial for maintaining rhythmic activity involved in cognitive and affective functions. Understanding specific mechanisms of thalamocortical circuit activity might lead to therapeutic interventions for individuals with FXS and other conditions characterized by thalamic dysrhythmia.
神经发育障碍脆性X综合征（FXS）是由FMR1基因的高甲基化导致的，这会阻止FMRP蛋白的产生。FMRP调节多种蛋白质的表达和功能，包括电压门控离子通道，如超极化激活的环核苷酸门控（HCN）通道，这些通道是丘脑结构中有节奏活动所必需的。丘脑皮质病理学，特别是涉及背内侧丘脑（MD）的病理学，已被认为与FXS等神经发育障碍有关。MD与内侧前额叶皮质（mPFC）的连接对于执行功能（如工作记忆和社会行为）至关重要，而这些功能在FXS中会受到破坏。我们使用逆行标记和离体脑片全细胞电生理学相结合的方法，对40只野生型和42只Fmr1基因敲除雄性小鼠进行研究，以探讨Fmr1基因缺失如何影响投射到mPFC的外侧（MD-L）和内侧（MD-M）MD神经元（MD→mPFC神经元）的内在细胞特性。在MD-L神经元中，Fmr1基因敲除降低了HCN介导的膜特性电压凹陷和膜超极化后电位。我们还发现，在复杂爆发和低阈值尖峰中，反弹尖峰时间都出现了延迟。在Fmr1基因敲除小鼠中，MD-L→mPFC神经元中HCN通道活性的降低损害了HCN介导的膜电位调节的时间和幅度。反应时间的变化可能会对Fmr1基因敲除的丘脑皮质回路中的节律传播产生不利影响。MD丘脑神经元对于维持参与认知和情感功能的节律活动至关重要。了解丘脑皮质回路活动的具体机制可能会为FXS患者和其他以丘脑节律异常为特征的疾病带来治疗干预措施。
