Dissecting the age-related decline on spatial learning and memory tasks in rodent models: N-methyl-D-aspartate receptors and voltage-dependent Ca2+ channels in senescent synaptic plasticity

Abstract

In humans, heterogeneity in the decline of hippocampal-dependent episodic memory is observed during aging. Rodents have been employed as models of age-related cognitive decline and the spatial water maze has been used to show variability in the emergence and extent of impaired hippocampal-dependent memory. Impairment in the consolidation of intermediate-term memory for rapidly acquired and flexible spatial information emerges early, in middle-age. As aging proceeds, deficits may broaden to include impaired incremental learning of a spatial reference memory. The extent and time course of impairment has been be linked to senescence of calcium (Ca2+) regulation and Ca2+-dependent synaptic plasticity mechanisms in region CA1. Specifically, aging is associated with altered function of N-methyl-D-aspartate receptors (NMDARs), voltage-dependent Ca2+ channels (VDCCs), and ryanodine receptors (RyRs) linked to intracellular Ca2+ stores (ICS). In young animals, NMDAR activation induces long-term potentiation of synaptic transmission (NMDAR-LTP), which is thought to mediate the rapid consolidation of intermediate-term memory. Oxidative stress, starting in middle-age, reduces NMDAR function. In addition, VDCCs and ICS can actively inhibit NMDAR-dependent LTP and oxidative stress enhances the role of VDCC and RyR-ICS in regulating synaptic plasticity. Blockade of L-type VDCCs promotes NMDAR-LTP and memory in older animals. Interestingly, pharmacological or genetic manipulations to reduce hippocampal NMDAR function readily impair memory consolidation or rapid learning, generally leaving incremental learning intact. Finally, evidence is mounting to indicate a role for VDCC-dependent synaptic plasticity in associative learning and the consolidation of remote memories. Thus, VDCC-dependent synaptic plasticity and extrahippocampal systems may contribute to incremental learning deficits observed with advanced aging.

Initial Evaluation of 18F-GE-179, a Putative PET Tracer for Activated N-Methyl d-Aspartate Receptors

“…A positive correlation between V T and age was observed and so future studies, especially if involving poorly matched subgroups, should model this as a covariate in the analyses. This finding appears at odds with the agerelated declines in cerebral blood flow (39) and NMDA receptor function (40). However, it is possible that the relationship between 18 F-GE-179 V T and age is nonlinear.…”

Integrity of mGluR-LTD in the Associative/Commissural Inputs to CA3 Correlates with Successful Aging in Rats

“…Next we consider the possibility that reduced levels of neuromodulators in slices from aged rats limited the induction NMDAR-LTD. In CA1 and cortical synapses Gq-coupled receptors promote NMDAR-LTD (Choi et al, 2005;Huang et al, 2012), and this type of modulation is an attractive candidate substrate for the behavioral gating of LTD observed in vivo (Hagena and Manahan-Vaughan, 2011). We found that stimulation of ␣1 adrenergic receptors (coupled to Gq) with bath application of methoxamine (5 M during LFS), a manipulation that rescues the loss of NMDAR-LTD in the visual cortex after dark rearing (Guo et al, 2012), did not improve NMDAR-LTD in slices from AU rats (96.50 Ϯ 1.68% of LTD, n ϭ 6 slices, 2 rats; data not shown).…”

“…However, the central premise-that the NR2b subunit promotes LTD over LTP-has been challenged by several studies reporting that NR2b-containing receptors are not essential for LTD (Morishita et al, 2007), but rather promote LTP over LTD (Philpot et al, 2003;Barria and Malinow, 2005). Another possibility has invoked an age-dependent change in intracellular Ca 2ϩ homeostasis as a basis for reduced LTP and enhanced LTD, which is observed in the SC3 CA1 pathway of some rat models of aging (Burke and Barnes, 2006;Oh et al, 2010;Foster, 2012). Note, however, that both altered NMDAR subunit composition and altered Ca 2ϩ homeostasis would predict that NMDAR-LTP should also be affected.…”

“…A link between hyperactivity and impaired synaptic plasticity is further suggested by studies in sensory cortices, where levels of neural activity can profoundly alter the induction of LTD. In particular, manipulations that reduce the GABAergic inhibitory tone and increase cortical excitability impair the induction of NMDAR-dependent LTD; conversely, restoring normal cortical excitability also restores LTD induction (Choi et al, 2002). Thus, if a similar type of regulation operates in CA3, increased excitability could impair synaptic plasticity, contributing to network dysfunction.…”

“…Previous research, primarily conducted at the Schaffer collateral inputs to CA1 cells (SC3 CA1) has identified alterations in LTP and LTD that are associated with age-related cognitive decline (Landfield and Lynch, 1977;Deupree et al, 1993;Norris et al, 1996;Shankar et al, 1998;Schulz et al, 2002;Tombaugh et al, 2002;Burke and Barnes, 2006;Boric et al, 2008). While the SC3 CA1 pathway has been a preferred model to study the cellular basis of cognitive impairment because the mechanisms of LTP and LTD have been thoroughly characterized in normal young rats, a wealth of evidence at both the systems and molecular levels indicates that differences in cognitive aging are strongly evident in hippocampal circuits and subregions outside CA1.…”