Horovitz David J, Askins Laura A, Regnier Grace M, McQuail Joseph A
Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, USA.
Neurobiol Aging. 2025 Apr;148:80-97. doi: 10.1016/j.neurobiolaging.2025.01.010. Epub 2025 Feb 7.
Age-related cognitive decline varies widely among individuals, with some showing resilience despite older age. This study examines synaptic markers of glutamatergic and GABAergic neurotransmission in the hippocampus and cortex of older rats with differing cognitive abilities, aiming to uncover mechanisms that contribute to cognitive resilience. We observed significant age-related reductions in vesicular glutamate transporter VGluT1, particularly in the stratum oriens (SO), radiatum (SR), and lacunosum-moleculare (SLM) of the dorsal CA3 and SLM of the dorsal CA1. Furthermore, loss of VGluT1 in the dorsal CA3-SLM correlated with severity of memory impairment. Higher levels of the vesicular GABA transporter (VGAT) were associated with better spatial learning in older rats, across several synaptic zones of the dorsal hippocampus, including the outer molecular layer of the dentate gyrus (DG), and the SO, SR, SLM, and pyramidal cell layers of both CA3 and CA1. This suggests that enhanced inhibitory neurotransmission specific to the dorsal aspect of the hippocampus may protect against age-related cognitive decline. While the dorsal hippocampus showed consistent age- and memory-related changes, markers in the ventral hippocampus remained largely intact. In the perirhinal cortex, VGluT1 declined with no changes in VGAT, while both markers remained unchanged in other cortical regions, including the lateral entorhinal, retrosplenial, and posterior parietal cortices. These findings highlight region-specific patterns of synaptic aging as potential markers of brain and cognitive reserve.
与年龄相关的认知衰退在个体间差异很大，一些人尽管年事已高但仍表现出认知弹性。本研究检测了具有不同认知能力的老年大鼠海马体和皮质中谷氨酸能和γ-氨基丁酸能神经传递的突触标志物，旨在揭示有助于认知弹性的机制。我们观察到囊泡谷氨酸转运体VGluT1随年龄增长显著减少，尤其是在背侧CA3的原层（SO）、辐射层（SR）和分子层（SLM）以及背侧CA1的SLM。此外，背侧CA3-SLM中VGluT1的缺失与记忆障碍的严重程度相关。在老年大鼠中，较高水平的囊泡γ-氨基丁酸转运体（VGAT）与较好的空间学习能力相关，涉及背侧海马体的多个突触区域，包括齿状回（DG）的外分子层以及CA3和CA1的SO、SR、SLM和锥体细胞层。这表明海马体背侧特异性增强的抑制性神经传递可能预防与年龄相关的认知衰退。虽然背侧海马体显示出与年龄和记忆相关的一致变化，但腹侧海马体中的标志物基本保持完整。在嗅周皮质中，VGluT1减少而VGAT无变化，而在其他皮质区域，包括外侧内嗅皮质、压后皮质和顶叶后皮质，这两种标志物均保持不变。这些发现突出了突触衰老的区域特异性模式，作为大脑和认知储备的潜在标志物。
