Dentate Granule Cells Are Hyperexcitable in the TgF344-AD Rat Model of Alzheimer's Disease.
Dentate Granule Cells Are Hyperexcitable in the TgF344-AD Rat Model of Alzheimer's Disease.
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DOI：
10.3389/fnsyn.2022.826601
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发表时间：
2022
影响因子：
3.7
通讯作者：
McMahon, Lori L.
中科院分区：
文献类型：
--
作者：
Smith, Lindsey A.;Goodman, Anthoni M.;McMahon, Lori L.
齿状回既是海马信号处理的关键守门人，也是阿尔茨海默病（AD）中最早出现功能障碍的脑区之一。因此，通过齿状回的兴奋和抑制的适当平衡是早期AD的机制研究和治疗干预的令人信服的目标。以前，我们报告了增加长时程增强（LTP）幅度在内侧穿通路径齿状颗粒细胞（MPP-DGC）突触切片从男性和急性卵巢切除的女性TgF 344-AD大鼠相比，野生型（Wt）早在6个月的年龄，伴随着增加稳态突触后去极化在高频刺激用于诱导可塑性。随后，我们发现β-肾上腺素能受体（β-AR）功能的增强驱动了LTP幅度的增加，但稳态去极化的增加仅部分归因于β-AR激活。由于我们先前报道在棘密度或突触前释放概率方面没有可检测到的差异，我们考虑了DGC本身可能具有修饰的被动或主动膜特性的可能性，这可能有助于高频刺激期间电荷转移的显著增加。使用脑切片电生理学从6个月大的雌性大鼠急性卵巢切除，以消除由于波动的血浆雌二醇的变化，我们发现显着的变化，被动膜性能和主动膜性能导致增加DGC兴奋性TGF 344-AD大鼠。具体地，TgF 344-AD DGC具有增加的输入电阻和降低的基强度、降低的下垂和增加的动作电位（AP）尖峰调节。重要的是，我们发现对于相同量的去极化电流注入，与Wt大鼠相比，来自TgF 344-AD的DGC具有更大幅度的电压响应，其伴随着减少的延迟来激发第一动作电位，表明TgF 344-AD DGC膜更易兴奋。总而言之，TgF 344-AD大鼠的DGC更容易兴奋，这可能导致高频突触激活期间去极化增强。
The dentate gyrus is both a critical gatekeeper for hippocampal signal processing and one of the first brain regions to become dysfunctional in Alzheimer's disease (AD). Accordingly, the appropriate balance of excitation and inhibition through the dentate is a compelling target for mechanistic investigation and therapeutic intervention in early AD. Previously, we reported an increased long-term potentiation (LTP) magnitude at medial perforant path-dentate granule cell (MPP-DGC) synapses in slices from both male and acutely ovariectomized female TgF344-AD rats compared with wild type (Wt) as early as 6 months of age that is accompanied by an increase in steady-state postsynaptic depolarization during the high-frequency stimulation used to induce plasticity. Subsequently, we found that heightened function of β-adrenergic receptors (β-ARs) drives the increase in the LTP magnitude, but the increase in steady-state depolarization was only partially due to β-AR activation. As we previously reported no detectable difference in spine density or presynaptic release probability, we entertained the possibility that DGCs themselves might have modified passive or active membrane properties, which may contribute to the significant increase in charge transfer during high-frequency stimulation. Using brain slice electrophysiology from 6-month-old female rats acutely ovariectomized to eliminate variability due to fluctuating plasma estradiol, we found significant changes in passive membrane properties and active membrane properties leading to increased DGC excitability in TgF344-AD rats. Specifically, TgF344-AD DGCs have an increased input resistance and decreased rheobase, decreased sag, and increased action potential (AP) spike accommodation. Importantly, we found that for the same amount of depolarizing current injection, DGCs from TgF344-AD compared with Wt rats have a larger magnitude voltage response, which was accompanied by a decreased delay to fire the first action potential, indicating TgF344-AD DGCs membranes are more excitable. Taken together, DGCs in TgF344-AD rats are more excitable, which likely contributes to the heightened depolarization during high-frequency synaptic activation.
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DOI：
10.1186/s13195-018-0346-2
发表时间：
2018-02-07
期刊：
Alzheimer's research & therapy
影响因子：
--
作者：
Muñoz-Moreno E;Tudela R;López-Gil X;Soria G
通讯作者：
Soria G
影响因子：
15.1
作者：
Do Carmo S;Cuello AC
通讯作者：
Cuello AC
DOI：
10.1073/pnas.94.4.1488
发表时间：
1997-02-18
影响因子：
11.1
作者：
Airaksinen, MS;Eilers, J;Meyer, M
通讯作者：
Meyer, M
影响因子：
5.5
作者：
MADISON, DV;NICOLL, RA
通讯作者：
NICOLL, RA
影响因子：
16.2
作者：
Palop, Jorge J.;Chin, Jeannie;Mucke, Lennart
通讯作者：
Mucke, Lennart