Valdivia Gonzalo, Ardiles Alvaro O, Idowu Abimbola, Salazar Claudia, Lee Hey-Kyoung, Gallagher Michela, Palacios Adrian G, Kirkwood Alfredo
Mind/Brain Institute and Department of Neurosciences, Johns Hopkins University, Baltimore, MD, United States.
Centro Interdisciplinario de Neurociencia de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile.
Front Synaptic Neurosci. 2023 Mar 2;15:1123294. doi: 10.3389/fnsyn.2023.1123294. eCollection 2023.
Long-term potentiation (LTP) and depression (LTD) are currently the most comprehensive models of synaptic plasticity models to subserve learning and memory. In the CA1 region of the hippocampus LTP and LTD can be induced by the activation of either NMDA receptors or mGluR5 metabotropic glutamate receptors. Alterations in either form of synaptic plasticity, NMDAR-dependent or mGluR-dependent, are attractive candidates to contribute to learning deficits in conditions like Alzheimer's disease (AD) and aging. Research, however, has focused predominantly on NMDAR-dependent forms of LTP and LTD. Here we studied age-associated changes in mGluR-dependent LTP and LTD in the APP/PS1 mouse model of AD and in , a rodent model of aging that exhibits features of AD. At 2 months of age, APP/PS1 mouse exhibited robust mGluR-dependent LTP and LTD that was completely lost by the 8th month of age. The expression of mGluR protein in the hippocampus of APP/PS1 mice was not affected, consistent with previous findings indicating the uncoupling of the plasticity cascade from mGluR5 activation. In , the average mGluR-LTD magnitude is reduced by half by the 3 year of age. In aged individuals, the reduced mGluR-LTD correlated with reduced performance in a radial arm maze task. Altogether these findings support the idea that the preservation of mGluR-dependent synaptic plasticity is essential for the preservation of learning capacity during aging.
长期增强（LTP）和长期抑制（LTD）是目前用于支持学习和记忆的最全面的突触可塑性模型。在海马体的CA1区域，LTP和LTD可由NMDA受体或mGluR5代谢型谷氨酸受体的激活诱导产生。突触可塑性的任何一种形式（NMDAR依赖性或mGluR依赖性）的改变，都是导致阿尔茨海默病（AD）和衰老等情况下学习缺陷的有吸引力的候选因素。然而，研究主要集中在NMDAR依赖性形式的LTP和LTD上。在这里，我们研究了AD的APP/PS1小鼠模型以及表现出AD特征的衰老啮齿动物模型中，mGluR依赖性LTP和LTD与年龄相关的变化。在2个月大时，APP/PS1小鼠表现出强大的mGluR依赖性LTP和LTD，但在8个月大时完全丧失。APP/PS1小鼠海马体中mGluR蛋白的表达未受影响，这与之前表明可塑性级联与mGluR5激活解偶联的研究结果一致。在衰老的啮齿动物模型中到3岁时，平均mGluR-LTD幅度减半。在老年个体中，mGluR-LTD降低与放射状臂迷宫任务中的表现下降相关联。总之，这些发现支持了这样一种观点：在衰老过程中，维持mGluR依赖性突触可塑性对于维持学习能力至关重要。
