Research reportAge-related working memory impairment is correlated with increases in the L-type calcium channel protein α1D (Cav1.3) in area CA1 of the hippocampus and both are ameliorated by chronic nimodipine treatment
Introduction
L-VSCCs are voltage sensitive channels that mediate long-lasting Ca2+ currents in response to depolarization in excitable cells. Brain L-VSCCs consist of five subunits: α1, α2, β, γ and δ [24], [42], [50]. The α1 subunits form the ion-conducting pore of the channel and contain the binding sites for the dihydropyridine class of L-VSCC antagonists [7]. Two different brain L-VSCC α1 subunits have been identified: α1C (Cav1.2) and α1D (Cav1.3) [25], [48]. Increasing evidence suggests that L-VSCC currents are elevated in CA1 neurons of the hippocampus in aged rats and rabbits [6], [37], [47], [51], [52], perhaps due to increases in the density of L-VSCCs in neuronal cell membranes [6], [52]. Indeed, α1D mRNA is increased in area CA1 of aged rats [20] and L-VSCC currents correlate with levels of α1D mRNA in single neurons [10]. We have recently shown that α1D protein is selectively increased in area CA1 of the aged rat hippocampus while expression of the alternative pore forming subunit α1C remains unchanged [54].
It has been proposed that age-related deficits in cognitive processing are due to dysfunction of one or more of the components involved in hippocampal synaptic plasticity. Long-term potentiation (LTP) is a synapse-specific, activity-dependent enhancement in synaptic efficacy [5] that can be induced at hippocampal synapses. LTP is a favored candidate for a cellular mechanism of memory [4] and, like memory, some forms of LTP decline with advancing age [34]. LTP induction requires Ca2+ influx through NMDAR [4], or L-VSCC [36] but the mechanism for induction of LTP by L-VSCC appears to be distinct from LTP resulting from NMDAR activation [8], [9], [19].
Interestingly, while NMDAR-dependent LTP is decreased in area CA1 of aged rats [11], [34], L-VSCC-dependent LTP is increased [47]. However, the direct relationship between L-VSCC current increases and memory formation remains unclear, although some data suggest that excessive Ca2+ influx through L-VSCCs may in fact be detrimental to memory formation. For instance, Landfield et al. reported that increases in L-VSCC currents in area CA1 of the aged hippocampus correlated with degree of learning impairment on a hippocampal-dependent task [52]. Furthermore, the L-type calcium channel antagonist nimodipine (NIM) has been shown to enhance memory in both young and aged animals or animals with experimentally-induced ischemia or hypoxia [2], [13], [14], [32], [41], [55]. However, the molecular basis for these effects remains elusive and questions regarding the long-term neurobiological effects of chronic NIM treatment remain unanswered.
The aim of the current study was twofold: (1) to investigate the role of α1D expression in age-related working memory decline, and (2) to investigate whether chronic treatment with the L-VSCC antagonist nimodipine (NIM) affects levels of the L-type VSCC α1 subunits or other proteins known to be involved in hippocampal-dependent memory, i.e. the NMDA-R subunits NR2A and NR2B, and CaMKII, in brains of aged rats.
Section snippets
Animals
All young (4 months old) and aged (24 months old) Fischer 344 rats were obtained from the National Institutes of Aging colony at Harlan Laboratories under a pilot study award (LMV and MBD). In accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals, every effort was made to minimize the quantity and suffering of the rats employed in this study. Accordingly, rats were housed in a climate controlled environment with a 12-h light–dark cycle (lights on at
Experiment 1
Young and aged rats were trained to locate a hidden platform in one of 12 arms of the RAWM. The platform location changed daily and thus the rats were required to learn the platform’s location on each testing day. Following 7 days of pretraining, rats underwent testing for 4 days in a no-delay condition where the rats were re-released into the maze after a 30-s inter-trial interval for four successive trials. Fig. 1A shows the average number of errors (arms entered) the rats made in locating
Discussion
We have used the RAWM to demonstrate spatial memory impairments in aged rats. In the first study, aged rats performed as well as young rats when inter-trial intervals were short and working memory load was low. However, after a 3-h delay aged rats demonstrated significant impairments in memory for the location of the hidden platform. In these aged rats, expression of α1D protein was greatly increased in area CA1 of the hippocampus, an area thought to be critical for spatial memory encoding [22]
Acknowledgements
This research was supported by grants AG04418 (MDB), AG00961 (MMH), and a National Institutes of Aging pilot study award (LMV and MDB). We thank Dr. Linda Crnic and Ms. Rachel Alvestad for critically reading this manuscript.
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Present address: Dept. Neurodegenerative Disorders, H. Lundbeck A/S, Offiliasuej 9, 2500 Valby, Denmark.