Lopes Cátia R, Amaral Inês M, Pereira Marlene F, Lopes João P, Madeira Daniela, Canas Paula M, Cunha Rodrigo A, Agostinho Paula
Center for Neuroscience and Cell Biology (CNC), Coimbra, Portugal.
Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
J Neurochem. 2022 Mar;160(5):556-567. doi: 10.1111/jnc.15575. Epub 2022 Feb 12.
Amyloid-β peptides (Aβ) accumulate in the brain since early Alzheimer's disease (AD) and dysregulate hippocampal synaptic plasticity, the neurophysiological basis of memory. Although the relationship between long-term potentiation (LTP) and memory processes is well established, there is also evidence that long-term depression (LTD) may be crucial for learning and memory. Alterations in synaptic plasticity, namely in LTP, can be due to communication failures between astrocytes and neurons; however, little is known about astrocytes' ability to control hippocampal LTD, particularly in AD-like conditions. We now aimed to test the involvement of astrocytes in changes of hippocampal LTP and LTD triggered by Aβ , taking advantage of L-α-aminoadipate (L-AA), a gliotoxin that blunts astrocytic function. The effects of Aβ exposure were tested in two different experimental paradigms: ex vivo (hippocampal slices superfusion) and in vivo (intracerebroventricular injection), which were previously validated to impair memory and hippocampal synaptic plasticity, two features of early AD. Blunting astrocytic function with L-AA reduced LTP and LTD amplitude in hippocampal slices from control mice, but the effect on LTD was less evident, suggesting that astrocytes have a greater influence on LTP than on LTD under non-pathological conditions. However, under AD conditions, blunting astrocytes did not consistently alter the reduction of LTP magnitude, but reverted the LTD-to-LTP shift caused by both ex vivo and in vivo Aβ exposure. This shows that astrocytes were responsible for the hippocampal LTD-to-LTP shift observed in early AD conditions, reinforcing the interest of strategies targeting astrocytes to restore memory and synaptic plasticity deficits present in early AD.
自早期阿尔茨海默病（AD）起，β淀粉样肽（Aβ）就在大脑中积累，并使海马体突触可塑性失调，而突触可塑性是记忆的神经生理基础。尽管长期增强（LTP）与记忆过程之间的关系已得到充分确立，但也有证据表明长期抑制（LTD）可能对学习和记忆至关重要。突触可塑性的改变，即LTP的改变，可能是由于星形胶质细胞与神经元之间的通讯故障所致；然而，关于星形胶质细胞控制海马体LTD的能力，尤其是在类AD条件下，人们知之甚少。我们现在旨在利用L-α-氨基己二酸（L-AA）（一种可削弱星形胶质细胞功能的神经毒素）来测试星形胶质细胞在Aβ引发的海马体LTP和LTD变化中的作用。在两种不同的实验范式中测试了Aβ暴露的影响：离体（海马体切片灌流）和体内（脑室内注射），这两种范式先前已被证实会损害记忆和海马体突触可塑性，而这是早期AD的两个特征。用L-AA削弱星形胶质细胞功能会降低对照小鼠海马体切片中的LTP和LTD幅度，但对LTD的影响不太明显，这表明在非病理条件下，星形胶质细胞对LTP的影响比对LTD的影响更大。然而，在AD条件下，削弱星形胶质细胞并没有持续改变LTP幅度的降低，但却逆转了离体和体内Aβ暴露所导致的LTD向LTP的转变。这表明星形胶质细胞是早期AD条件下观察到的海马体LTD向LTP转变的原因，这增强了针对星形胶质细胞的策略对于恢复早期AD中存在的记忆和突触可塑性缺陷的意义。
