Rodemer William, Ra Irene, Jia Elizabeth, Gujral Jaskeerat, Zhang Bin, Hoxha Kevt'her, Xing Bo, Mehta Sanya, Farag Madona, Porta Silvia, Jensen Frances E, Talos Delia M, Lee Virginia M-Y
bioRxiv. 2024 Sep 24:2024.09.24.612703. doi: 10.1101/2024.09.24.612703.
Neuronal hyperexcitability is a hallmark of amyotrophic lateral sclerosis (ALS) but its relationship with the TDP-43 aggregates that comprise the predominant pathology in over 90% of ALS cases remains unclear. Emerging evidence in tissue and slice culture models indicate that TDP-43 pathology induces neuronal hyperexcitability suggesting it may be responsible for the excitotoxicity long believed to be a major driver of ALS neuron death. Here, we characterized hyperexcitability and neurodegeneration in the hippocampus of doxycycline-regulatable rNLS8 mice (NEFH-tTA x tetO-hTDP-43ΔNLS), followed by treatment with AAV encoded DREADDs and anti-seizure medications to measure the effect on behavioral function and neurodegeneration. We found that approximately half of the CA3 neurons in the dorsal hippocampus are lost between 4 and 6 weeks after TDP-43ΔNLS induction. Neurodegeneration was preceded by selective hyperexcitability in the mossy fiber - CA3 circuit, leading us to hypothesize that glutamate excitotoxicity may be a significant contributor to neurodegeneration in this model. Interestingly, hippocampal injection of AAV encoded inhibitory DREADDs (hM4Di) and daily activation with CNO ligand rescued anxiety deficits on elevated zero maze (EZM) but did not reduce neurodegeneration. Therapeutic doses of the anti-seizure medications, valproic acid and levetiracetam, did not improve behavior or prevent neurodegeneration. These results highlight the complexity of TDP-43 - induced alterations to neuronal excitability and suggest that whereas targeting hyperexcitability can meliorate some behavioral deficits, it may not be sufficient to halt or slow neurodegeneration in TDP-43-related proteinopathies.
Cytoplasmic aggregates of TAR DNA Binding Protein 43 (TDP-43) are the predominant pathology in over 90% of Amyotrophic lateral sclerosis (ALS) and the majority of frontotemporal lobar degeneration (FTLD-TDP) cases. Understanding how TDP-43 pathology promotes neurodegeneration may lead to therapeutic strategies to slow disease progression in humans. Recent reports in mouse and cell culture models suggest loss-of-normal TDP-43 function may drive neuronal hyperexcitability, a key physiological hallmark of ALS and possible contributor to neurodegeneration. In this study, we identified region-specific hyperexcitability that precedes neurodegeneration in the inducible rNLS8 TDP-43 mouse model. Suppressing hyperexcitability with chemogenetics improved behavioral function but did not reduce hippocampal neuron loss. Anti-seizure medications had no beneficial effects suggesting directly targeting hyperexcitability may not be therapeutically effective.
神经元兴奋性过高是肌萎缩侧索硬化症（ALS）的一个标志，但其与TDP-43聚集体（在超过90%的ALS病例中构成主要病理特征）之间的关系仍不清楚。组织和切片培养模型中的新证据表明，TDP-43病理改变会导致神经元兴奋性过高，这表明它可能是长期以来被认为是ALS神经元死亡主要驱动因素的兴奋性毒性的原因。在此，我们对强力霉素可调节的rNLS8小鼠（NEFH-tTA x tetO-hTDP-43ΔNLS）海马中的兴奋性过高和神经退行性变进行了表征，随后用腺相关病毒编码的DREADDs和抗癫痫药物进行治疗，以测量对行为功能和神经退行性变的影响。我们发现，在诱导TDP-43ΔNLS后的4至6周内，背侧海马中约一半的CA3神经元丢失。在苔藓纤维-CA3回路中，神经退行性变之前存在选择性兴奋性过高，这使我们推测谷氨酸兴奋性毒性可能是该模型中神经退行性变的一个重要因素。有趣的是，海马注射腺相关病毒编码的抑制性DREADDs（hM4Di）并每日用CNO配体激活，可挽救高架零迷宫（EZM）上的焦虑缺陷，但并未减少神经退行性变。抗癫痫药物丙戊酸和左乙拉西坦的治疗剂量并未改善行为或预防神经退行性变。这些结果突出了TDP-43诱导的神经元兴奋性改变的复杂性，并表明尽管针对兴奋性过高可以改善一些行为缺陷，但可能不足以阻止或减缓TDP-43相关蛋白病中的神经退行性变。
TAR DNA结合蛋白43（TDP-43）的细胞质聚集体是超过90%的肌萎缩侧索硬化症（ALS）和大多数额颞叶痴呆（FTLD-TDP）病例中的主要病理特征。了解TDP-43病理如何促进神经退行性变可能会带来减缓人类疾病进展的治疗策略。小鼠和细胞培养模型中的最新报告表明，正常TDP-43功能的丧失可能导致神经元兴奋性过高，这是ALS的一个关键生理标志，也是神经退行性变的可能因素。在本研究中，我们在可诱导的rNLS8 TDP-43小鼠模型中确定了神经退行性变之前的区域特异性兴奋性过高。用化学遗传学抑制兴奋性过高可改善行为功能，但并未减少海马神经元丢失。抗癫痫药物没有有益效果，这表明直接针对兴奋性过高可能在治疗上无效。
