Official websites use. Share sensitive information only on official, secure websites. While most of these genes have weak effects, using a polygenic risk profile score RPS approach — a method that allows exploration of the influence of the cumulative effect of risk alleles - we and others have shown the negative influence of LOAD risk genes on brain structure Chauhan et al.
Identifying mechanisms, particularly genetic mechanisms that confer resilience to the detrimental effect of LOAD related risk genes on brain structure and function could provide a viable avenue to identify novel therapeutic targets for LOAD. To that end, in the current study, we explored the role of polymorphisms in the gene encoding Reelin RELN , a glycoprotein that has been shown to be critical for neuronal development and synaptic plasticity Kramer et al.
Studies have shown that normal RELN levels are necessary to prevent abnormal phosphorylation of tau Ohkubo et al. A region of interest analysis was performed using bilateral hippo-parahippocampal masks from the Anatomical Automatic Labeling Atlas. There were no significant positive correlations. None of the other RELN polymorphisms tested showed a significant effect. Conclusions: Our results, while showing a cumulative deleterious effect of several LOAD related risk genes on hippocampal function in healthy volunteers, also illustrate that this relationship is modulated by a missense SNP rs in the RELN gene.
In particular, only the minor allele C carriers show a significant negative relationship between RPS and hippocampal function suggesting that homozygosity for the G allele in this polymorphism could potentially confer a protective effect. Background: Working memory involves the ability to briefly maintain context-specific information in mind and to use this representational knowledge to guide current and future action. This form of short-term memory is supported by the prefrontal cortex PFC and is believed to rely on the ability of selectively tuned pyramidal neuron networks to persist in firing even after a to-be-remembered stimulus is removed from the environment.
Ionotropic glutamate receptors of the NMDA subtype are expressed on pyramidal neurons in the PFC, and altered activity at these receptors has been implicated in working memory deficits associated with both psychiatric disorders and normal aging. NMDA receptors are biochemically diverse heterotetramers comprised of an obligate NR1 subunit and variable NR2A or NR2B subunits, the latter of which can influence both the channel kinetics and localization of the receptor to synaptic versus extrasynaptic sites.
