Cognitive decline is associated with reduced reelin expression in the entorhinal cortex of aged rats

Department of Psychological and Brain Sciences, Johns Hopkins University, Baltimore, MD 21218, USA.
Cerebral Cortex (Impact Factor: 8.67). 02/2011; 21(2):392-400. DOI: 10.1093/cercor/bhq106
Source: PubMed

ABSTRACT Brain regions and neural circuits differ in their vulnerability to changes that occur during aging and in age-related neurodegenerative diseases. Among the areas that comprise the medial temporal lobe memory system, the layer II neurons of the entorhinal cortex, which form the perforant path input to the hippocampal formation, exhibit early alterations over the course of aging Reelin, a glycoprotein implicated in synaptic plasticity, is expressed by entorhinal cortical layer II neurons. Here, we report that an age-related reduction in reelin expression in the entorhinal cortex is associated with cognitive decline. Using immunohistochemistry and in situ hybridization, we observed decreases in the number of Reelin-immunoreactive cells and reelin messenger RNA expression in the lateral entorhinal cortex of aged rats that are cognitively impaired relative to young adults and aged rats with preserved cognitive abilities. The lateral entorhinal cortex of aged rats with cognitive impairment also exhibited changes in other molecular markers, including increased accumulation of phosphorylated tau and decreased synaptophysin immunoreactivity. Taken together, these findings suggest that reduced reelin expression, emanating from layer II entorhinal neurons, may contribute to network dysfunction that occurs during memory loss in aging.

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    • "In the context of aging, altered transcriptional regulation of genes that promote or are necessary for synaptic plasticity is associated with memory impairment in aged rodents (Blalock et al. 2003; Rowe et al. 2007; Haberman et al. 2011). Affected genes implicated in plasticity notably include the immediate-early genes HomerI1a, and Arc (activity regulated cytoskeleton-associated protein ), which are necessary for learning and memory (Penner et al. 2011), as well as zif268, bdnf (brain-derived neurotrophic factor ) (Hattiangady et al. 2005), and reelin (Stranahan et al. 2011). Data derived from a rodent model of neurocognitive aging in which old Long-Evans rats show individual variability in cognitive outcome highlight the marked changes in hippocampal gene transcription that occur in association with age-related memory impairment, thereby distinguishing neurobiological signatures that are specifically associated with age-related memory decline from changes coupled with chronological age, unrelated to cognitive outcome. "
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    • "The LEC appeared to be affected in aging more than the MEC, because there was reduced synaptophysin, decreased reelin and increased phosphorylated tau in LEC neurons in layer II of aged animals, when the MEC did not appear to be altered (Stranahan et al., 2010). Notably, some animals lacked abnormalities; when animals were tested using the Morris water maze, those rats with impairments had layer II defects, but the others that performed normally had no detectable changes in the EC (Stranahan et al., 2010). Although correlative, the results suggested that neurons in layer II, especially in LEC, could play an important role in age-related cognitive impairment. "
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    • "Rats were behaviorally categorized based on their performance in the hippocampus-dependent version of the water maze, as described (Stranahan et al., 2011). Aged rats that performed within the range of young, as measured by using an index score derived from proximity to the goal platform location during interpolated probe trials, were classified as aged-unimpaired (AU), whereas rats that performed outside of the range of young were designated aged-impaired (AI). "
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