Regular articleReelin in the Years: decline in the number of reelin immunoreactive neurons in layer II of the entorhinal cortex in aged monkeys with memory impairment
Introduction
The entorhinal cortex (EC), together with the hippocampus and anatomically related “rhinal” cortical areas, comprises a medial temporal lobe system critical for normal memory (Buckmaster et al., 2004, Insausti et al., 1987, van Strien et al., 2009). The EC is a pivotal bidirectional gateway in this system, funneling convergent neocortical input into the hippocampus, and relaying the output of hippocampal processing to adjacent rhinal areas and many of the same neocortical targets from which it receives input (Witter, 1993). Among the distinctive features of the EC, stellate cells in layer II that originate the perforant path projection to the hippocampus are robustly immunoreactive for the extracellular matrix glycoprotein reelin (Martinez-Cerdeno and Clasca, 2002, Pesold et al., 1998, Ramos-Moreno et al., 2006). Long known to play an important role in neuronal migration and positioning during development, growing evidence indicates that reelin signaling remains critical for normal brain function throughout the lifespan (for review see Stranahan et al., 2013). In young subjects, reelin signaling through apolipoprotein E receptors modulates long-term potentiation (LTP) and other measures of synaptic plasticity (Forster et al., 2010, Herz and Chen, 2006, Rogers and Weeber, 2008). Linking these anatomical and physiological observations, recent evidence demonstrates that blocking reelin's interaction with its receptors, specifically in the EC, impairs spatial memory mediated by the hippocampus (Stranahan et al., 2011a, Stranahan et al., 2011b). These findings are consistent with the view that, in multiple regions of the adult brain, reelin expression and signaling regulate synaptic structure and function critical for normal learning and memory (Brosda et al., 2011, Rogers et al., 2011, Rogers et al., 2013, Stranahan et al., 2011b, Weeber et al., 2002).
Disrupted reelin signaling has been implicated in a variety of conditions in which cognition is prominently affected, including schizophrenia and Alzheimer's disease (AD) (Guidotti et al., 2000, Herring et al., 2012, Impagnatiello et al., 1998, Kramer et al., 2011, Seripa et al., 2008). The links to AD are illuminating and raise the possibility that the reelin-positive phenotype of layer II EC neurons might contribute to their documented vulnerability early in the course of the disorder. Changes in reelin expression localized to EC-hippocampal circuitry have also been observed in association with age-related cognitive decline, a frequent prodromal feature of disease. In rats, for example, where the effects of aging can be examined in the absence of frank neurodegeneration, aged subjects with impaired hippocampal memory display a substantial decline in EC layer II reelin expression relative to both young adults and aged rats with intact memory (Stranahan et al., 2011a). Here, taking advantage of an established model of neurocognitive aging in old world macaques, we asked whether the vulnerability of reelin-positive EC-hippocampal circuitry in cognitive aging extends to the primate brain.
Section snippets
Animals
Seven young adult (8–10 years at the time of perfusion, mean = 8.9 years; 5 females, 2 males) and 14 aged (27–38 years, mean = 31.7 year old; 7 females, 7 males) rhesus monkeys (Macaca mulatta) were used in this study. Subjects were maintained and behaviorally tested as previously described (Rapp and Amaral, 1991) at the California National Primate Research Center, Davis, California. All experiments were carried out in accordance with The National Research Council's Guide for the Care and Use
Cognitive characterization
DNMS results for the young and aged monkeys tested here were similar to earlier reports (Moss et al., 1988, Presty et al., 1987, Rapp and Amaral, 1991, Shamy et al., 2006). Specifically, aged monkeys required many times the number of trials as young adults to acquire the nonmatching rule of the task with a short, 10-second delay (Fig. 1A; t(1,19) = 5.17, p = 0.001). With sufficient training, however, all subjects performed at or above the 90% correct learning criterion. The memory demands of
Discussion
The EC is anatomically positioned to influence memory capacities known to be vulnerable to aging and AD (Buckmaster et al., 2004). Reelin expression is enriched in superficial layers of the EC, and previous studies have reported that the number of these neurons is decreased in aged mice (Knuesel et al., 2009) and rats (Stranahan et al., 2011a) with memory impairments. This effect appears particularly pronounced in lateral portions of the EC, a cortical area arguably homologous to the
Disclosure statement
The authors have no actual or potential conflicts of interest.
Acknowledgements
This research was supported by NIH grant R37 AG10606, the California National Primate Research Center, and in part by the Intramural Research Program of the National Institute on Aging. The authors thank Michela Gallagher and Alexis Stranahan for helpful discussion, and Surya Bhamidipaty for technical development, early in the course of the project. Title credits: Steely Dan (Walter Becker and Donald Fagan, songwriters), Reelin’ in the Years, 1972.
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