Reduction in size of perforated postsynaptic densities in hippocampal axospinous synapses and age-related spatial learning impairments - PubMed (original) (raw)

Comparative Study

Daniel A Nicholson et al. J Neurosci. 2004.

Abstract

A central problem in the neurobiology of normal aging is why learning is preserved in some aged individuals yet impaired in others. To investigate this issue, we examined whether age-related deficits in spatial learning are associated with a reduction in postsynaptic density (PSD) area in hippocampal excitatory synapses (i.e., with a structural modification that is likely to have a deleterious effect on synaptic function). A hippocampus-dependent version of the Morris water maze task was used to separate Long-Evans male rats into young adult, aged learning-unimpaired, and equally aged learning-impaired groups. Axospinous synapses from the CA1 stratum radiatum were analyzed using systematic random sampling and serial section analyses. We report that aged learning-impaired rats exhibit a marked ( approximately 30%) and significant reduction in PSD area, whereas aged learning-unimpaired rats do not. The observed structural alteration involves a substantial proportion of perforated synapses but is not observed in nonperforated synapses. These findings support the notion that many hippocampal perforated synapses become less efficient in aged learning-impaired rats, which may contribute to cognitive decline during normal aging.

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Figures

Figure 1.

Figure 1.

Morphological subtypes of axospinous synapses from the rat CA1 stratum radiatum classified according to their PSD configuration. Electron micrographs of consecutive sections that, respectively, demonstrate a synapse with a fenestrated (_a_-f), horseshoe-shaped (_h_-m), or segmented (_o_-u) PSD, as well as two synapses (black and white arrows) with nonperforated PSDs (_w_-y). All micrographs containing PSD profiles are presented in each case. The synapses illustrated in _a_-_f, h_-m, or _o_-u belong to the perforated synaptic category because they exhibit a discontinuity(s) or perforation(s) in PSD profiles seen in consecutive sections (arrowheads). In contrast, nonperforated synapses show exclusively continuous PSD profiles in w-y. The presynaptic and postsynaptic elements of each synapse are labeled in a, h, o, and w by AT (axon terminal) and SP (spine). Two-dimensional reconstructions of PSD plates show their fenestrated (g), horseshoe-shaped (n), segmented (v), or nonperforated (z) configuration. Scale bars, 0.5 μm.

Figure 2.

Figure 2.

The area of PSDs in axospinous synapses from the CA1 stratum radiatum of YA, AU, and AI rats. Symbols represent the values for individual rats. Horizontal lines indicate the group means. a, Perforated PSDs have a significantly smaller area in AI rats relative to either YA (*) or AU (**) rats, whereas the latter two groups of animals do not differ significantly on this measure. The means ± SD for the YA, AU, and AI groups are 117.2 ± 12.3, 112.5 ± 11.7, and 82.5 ± 13.8 nm2× 103, respectively. b, Nonperforated PSD areas are not significantly different among the three groups of rats. The means ± SD for the YA, AU, and AI groups are 30.3 ± 3.8, 26.9 ± 2.4, and 29.0 ± 1.0 nm2× 103, respectively. Note that the scale of the ordinate axis differs from that in a.

Figure 3.

Figure 3.

Distribution of perforated PSDs with respect to their area in YA, AU, and AI rats. a, YA and AU rats have almost identical distributions. b, c, The distribution in AI rats is skewed toward smaller PSD areas compared with YA (b) and AU (c) rats.

Figure 4.

Figure 4.

The area of fenestrated, horseshoe-shaped, and segmented PSDs in the YA, AU, and AI groups. Symbols represent the values for individual rats. Horizontal lines indicate the group means. a, The fenestrated PSD area is significantly diminished in the AI group relative to the YA (*) and AU (**) groups. The means ± SD for the YA, AU, and AI groups are 116.0 ± 12.0, 114.5 ± 13.9, and 84.8 ± 14.3 nm2× 103, respectively. b, The horseshoe-shaped PSD area is significantly smaller in the AI group than in the YA (*) and AU (**) groups. The means ± SD for the YA, AU, and AI groups are 110.0 ± 14.0, 109.1 ± 10.6, and 78.2 ± 10.9 nm2× 103, respectively. c, The segmented PSD area is reduced in size in both aged groups (AU and AI) compared with the YA group (*). The AI group, however, also exhibits a significantly smaller area of segmented PSDs relative to the AU group (**). The means ± SD for the YA, AU, and AI groups are 147.9 ± 26.1, 113.8 ± 12.4, and 82.5 ± 26.8 nm2× 103, respectively.

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