Reduction in Size of Perforated Postsynaptic Densities in Hippocampal Axospinous Synapses and Age-Related Spatial Learning Impairments

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 (∼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.

[1]  D. Nicholson,et al.  Synapses with a segmented, completely partitioned postsynaptic density express more AMPA receptors than other axospinous synaptic junctions , 2004, Neuroscience.

[2]  M. Gallagher,et al.  Aging, spatial learning, and total synapse number in the rat CA1 stratum radiatum , 2004, Neurobiology of Aging.

[3]  R. Nicoll,et al.  AMPA Receptor Trafficking at Excitatory Synapses , 2003, Neuron.

[4]  Michela Gallagher,et al.  Effects of aging on the hippocampal formation in a naturally occurring animal model of mild cognitive impairment , 2003, Experimental Gerontology.

[5]  M. Ehlers.  Molecular morphogens for dendritic spines , 2002, Trends in Neurosciences.

[6]  M. Sheng,et al.  Dentritic spines : structure, dynamics and regulation , 2001, Nature Reviews Neuroscience.

[7]  Richard L. Huganir,et al.  Postsynaptic organisation and regulation of excitatory synapses , 2000, Nature Reviews Neuroscience.

[8]  M. Ehlers,et al.  Reinsertion or Degradation of AMPA Receptors Determined by Activity-Dependent Endocytic Sorting , 2000, Neuron.

[9]  M. Kennedy,et al.  Signal-processing machines at the postsynaptic density. , 2000, Science.

[10]  Y. Geinisman,et al.  Structural synaptic modifications associated with hippocampal LTP and behavioral learning. , 2000, Cerebral cortex.

[11]  P. Somogyi,et al.  NMDA Receptor Content of Synapses in Stratum Radiatum of the Hippocampal CA1 Area , 2000, The Journal of Neuroscience.

[12]  J F Disterhoft,et al.  Remodeling of hippocampal synapses after hippocampus‐dependent associative learning , 2000, The Journal of comparative neurology.

[13]  R. Nicoll,et al.  Long-term potentiation--a decade of progress? , 1999, Science.

[14]  Peter Somogyi,et al.  Cell Type and Pathway Dependence of Synaptic AMPA Receptor Number and Variability in the Hippocampus , 1998, Neuron.

[15]  R. Weinberg,et al.  Enhanced expression of AMPA receptor protein at perforated axospinous synapses , 1998, Neuroreport.

[16]  M. Gallagher,et al.  Preserved neuron number in the hippocampus of aged rats with spatial learning deficits. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Jens Christian Sørensen,et al.  Memory impaired aged rats: No loss of principal hippocampal and subicular neurons , 1996, Neurobiology of Aging.

[18]  P. Somogyi,et al.  High-resolution immunogold localization of AMPA type glutamate receptor subunits at synaptic and non-synaptic sites in rat hippocampus , 1995, Neuroscience.

[19]  F. Morrell,et al.  Hippocampal markers of age-related memory dysfunction: Behavioral, electrophysiological and morphological perspectives , 1995, Progress in Neurobiology.

[20]  F. Morrell,et al.  Structural synaptic correlate of long‐term potentiation: Formation of axospinous synapses with multiple, completely partitioned transmission zones , 1993, Hippocampus.

[21]  Y. Geinisman,et al.  Perforated axospinous synapses with multiple, completely partitioned transmission zones: Probable structural intermediates in synaptic plasticity , 1993, Hippocampus.

[22]  David G. Amaral,et al.  Individual differences in the cognitive and neurobiological consequences of normal aging , 1992, Trends in Neurosciences.

[23]  S. Palay,et al.  The Fine Structure of the Nervous System: Neurons and Their Supporting Cells , 1991 .

[24]  D. C. Howell.  Statistical Methods for Psychology , 1987 .

[25]  F. Morrell,et al.  Aged rats need a preserved complement of perforated axospinous synapses per hippocampal neuron to maintain good spatial memory , 1986, Brain Research.

[26]  D. Nicholson,et al.  Differences in the expression of AMPA and NMDA receptors between axospinous perforated and nonperforated synapses are related to the configuration and size of postsynaptic densities , 2004, The Journal of comparative neurology.

[27]  S. J. Martin,et al.  New life in an old idea: The synaptic plasticity and memory hypothesis revisited , 2002, Hippocampus.

[28]  N. Cohen.  From Conditioning to Conscious Recollection Memory Systems of the Brain. Oxford Psychology Series, Volume 35. , 2001 .

[29]  H. Eichenbaum,et al.  From Conditioning to Conscious Recollection , 2001 .

[30]  H. J. G. Gundersen,et al.  Unbiased stereological estimation of the total number of synapses in a brain region , 1996, Journal of neurocytology.

[31]  D.G. Jones,et al.  An Analysis of Contemporary Morphological Concepts of Synaptic Remodelling in the CNS: Perforated Synapses Revisited , 1995, Reviews in the neurosciences.

[32]  S. B. Kater,et al.  Dendritic spines: cellular specializations imparting both stability and flexibility to synaptic function. , 1994, Annual review of neuroscience.

[33]  G. Paxinos.  The Rat nervous system , 1985 .

[34]  A. Peters,et al.  The small pyramidal neuron of the rat cerebral cortex. The synapses upon dendritic spines. , 1969, Zeitschrift fur Zellforschung und mikroskopische Anatomie.