Age-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

Veng, Lone; Mesches, Michael H.; Browning, Michael

doi:10.1016/s0169-328x(02)00643-5

Cited by 125 publications

(117 citation statements)

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“…In fact, ␣ 1 1.3 mRNA levels are increased in 24-versus 13-month-old Fisher 344 rats (12,80). More recent work indicated that the protein level of ␣ 1 1.3 is up-regulated by 25% in the CA1 area without a change in ␣ 1 1.2 protein level (10,11). This up-regulation of Ca v 1.3 expression may contribute to the increase in L-type channel activity.…”

Section: Discussionmentioning

confidence: 95%

“…Ca 2ϩ influx through L-type channels is up-regulated Ͼ2-fold in hippocampal neurons of old versus adult rats (9). The hippocampus is crucial for learning and memory; however, the molecular basis for the increase in L-type channel activity during aging is not well defined, except for an Ϸ20% increase in Ca v 1.3 protein (10,11). We now show that cAMP-dependent protein kinase (PKA)-mediated phosphorylation of the L-type channel Ca v 1.2 increases Ͼ2-fold during aging and that it may underlie a substantial portion of the age-related increase in L-type channel activity.…”

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confidence: 99%

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Increased phosphorylation of the neuronal L-type Ca ²⁺ channel Ca _v 1.2 during aging

Davare

Hell

2003

Proc. Natl. Acad. Sci. U.S.A.

110

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An increase in Ca 2؉ influx through L-type Ca 2؉ channels is thought to contribute to neuronal dysfunctions that underlie senile symptoms and Alzheimer's disease. The molecular basis of the agedependent up-regulation in neuronal L-type Ca 2؉ channel activity is largely unknown. We show that phosphorylation of the L-type channel Ca v1.2 by cAMP-dependent protein kinase is increased >2-fold in the hippocampus of aged rats. The hippocampus is critical for learning and is one of the first brain regions to be affected in Alzheimer's disease. Phosphorylation of Ca v1.2 by cAMP-dependent protein kinase strongly enhances its activity. Therefore, increased Ca v1.2 phosphorylation may account for a substantial portion of the age-related rise in neuronal Ca 2؉ influx and its neuropathological consequences. C a 2ϩ regulates a variety of signaling pathways (1-3). Acute uncontrolled Ca 2ϩ influx can cause neuronal death by overstimulation of the N-methyl-D-aspartate (NMDA)-type glutamate receptor (4, 5). Chronic elevation of Ca 2ϩ influx has been implicated in age-associated neuronal loss and Alzheimer's disease (6, 7). The age-related learning impairment in rabbits is reversed by the specific L-type Ca 2ϩ channel blocker nimodipine (8). These observations indicate that elevation of L-type channel activity causes neuronal dysfunction during aging. Ca 2ϩ influx through L-type channels is up-regulated Ͼ2-fold in hippocampal neurons of old versus adult rats (9). The hippocampus is crucial for learning and memory; however, the molecular basis for the increase in L-type channel activity during aging is not well defined, except for an Ϸ20% increase in Ca v 1.3 protein (10, 11). We now show that cAMP-dependent protein kinase (PKA)-mediated phosphorylation of the L-type channel Ca v 1.2 increases Ͼ2-fold during aging and that it may underlie a substantial portion of the age-related increase in L-type channel activity.PKA increases L-type channel activity in neurons (13-16) and in the heart, where PKA-dependent stimulation of the cardiac L-type channel is crucial for the up-regulation of the heartbeat after adrenergic stimulation (17, 18 (19), and the auxiliary subunits ␣ 2 -␦, -␤, and -␥ (22). Only ␣ 1 1.2, and none of the auxiliary subunits, is required for the PKA-mediated increase in channel activity (23). ␣ 1 1.2 is phosphorylated in intact hippocampal neurons by PKA (24). The main phosphorylation site on ␣ 1 1.2 is serine 1928 (25, 26), which is important for the up-regulation of the channel activity by PKA (27). This site is close to the C terminus of ␣ 1 1.2, is present only in the full-length form of ␣ 1 1.2 (21), and is removed by the Ca 2ϩ -activated protease calpain after Ca 2ϩ influx through NMDA receptors (28). Calpain cleaves ␣ 1 1.2 Ϸ300 residues upstream of the C terminus in vitro (28). Deletion of the last 300-400 residues of ␣ 1 1.2 increases channel activity when expressed in Xenopus oocytes (29); therefore, calpain-mediated cleavage may permanently elevate Ca v 1.2 activity in vivo. Because calpain has been impli...

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Section: Discussionmentioning

confidence: 95%

mentioning

confidence: 99%

Increased phosphorylation of the neuronal L-type Ca ²⁺ channel Ca _v 1.2 during aging

Davare

Hell

2003

Proc. Natl. Acad. Sci. U.S.A.

110

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“…In the hippocampus, aging is accompanied by two major Ca ++ dysregulations: (1) an increase in Ca ++ influx through L-type voltage-dependent calcium channels (L-VDCC) (Thibault and Landfield 1996;Shankar et al 1998;Veng et al 2003) and (2) an increase in Ca ++ -induced Ca ++ release from the endoplasmic reticulum (Kumar and Foster 2004;Gant et al 2006). These changes were demonstrated to be responsible for several hippocampal electrophysiological changes, including increases in slow afterhyperpolarization and spike accommodation (Gant et al 2006).…”

Section: Wwwlearnmemorgmentioning

confidence: 99%

“…Using this type of protocol, it was demonstrated that, with aging, the VDCC-dependent component of LTP increased while its NMDAdependent component diminished (Shankar et al 1998). More precisely, the density of functional L-type VDCC increases in mammalian CA1 hippocampal neurons during aging (Thibault and Landfield 1996;Veng et al 2003). The loss of input specificity observed in aged animals could be related to this up- and thapsigargin (Tocris) were both prepared as concentrated stock solutions in dimethyl sulfoxide (DMSO) and then diluted to 0.1% in ACSF for nifedipine and to 0.01% in ACSF for thapsigargin to give their final concentrations.…”

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confidence: 99%

Synapse specificity of long-term potentiation breaks down with aging

Ris¹,

Godaux²

2007

Learn. Mem.

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Memory shows age-related decline. According to the current prevailing theoretical model, encoding of memories relies on modifications in the strength of the synapses connecting the different cells within a neuronal network. The selective increases in synaptic weight are thought to be biologically implemented by long-term potentiation (LTP). Here, we report that tetanic stimulation of afferent fibers in slices from 12-mo-old mice triggers an LTP not restricted to the activated synapses. This phenomenon, which can be anticipated to hinder memory encoding, is suppressed by blocking either L-type Ca ++ channels or Ca ++ -induced Ca ++ release, both well known to become disregulated with aging.During the normal aging process, humans and animals experience age-related memory decline (Bach et al. 1999;Rosenzweig and Barnes 2003). Historically, it was thought that the primary contribution to the etiology of this decline was a massive loss of neurons in all the cortical layers and in the hippocampus (Brody 1955;Scheibel et al. 1976;Scheibel 1979). However, when it became possible to eliminate many of the confounding factors of the previous studies, this was proved to be a misconception (Burke and Barnes 2006). Nowadays, a great number of studies have identified multiple changes in Ca ++ -related electrophysiological processes as consistent biomarkers of aging (Landfield and Pitler 1984;Thibault and Landfield 1996;Norris et al. 1998;Thibault et al. 2001;Gant et al. 2006). One of the current prevailing hypotheses is that those Ca ++ dysregulations underlie many aspects of aging. However, the potential link between agerelated Ca ++ dysregulations and memory decline is still missing.For neurocomputing theorists, every memory is encoded in a neuronal network thanks to a change in the distribution of its synaptic weights (Zipser and Andersen 1988). Among the possible biological mechanisms, long-term potentiation (LTP) is the favored candidate to be at the basis of memory storage because this activity-induced increase in synaptic strength is (1) durable and (2) input-selective (restricted to the activated synapses). In the hippocampal synapses between Schaffer collaterals and CA1 pyramidal neurons, a single train of tetanic stimulation triggers a short-lasting LTP (S-LTP), which lasts 1-2 h, whereas multiple trains induce a long-lasting LTP (L-LTP) lasting >4 h (Huang and Kandel 1994;Abel et al. 1997). Potential age-related LTP defects have been sought out in the past. It has been reported that S-LTP in area CA1 from aged animals was normal when supra-threshold stimulation parameters were used (Moore et al. 1993;Burke and Barnes 2006) and showed deficits only when peri-threshold stimulation was applied (Barnes et al. 1992;Burke and Barnes 2006). The L-LTP triggered by multiple trains has been reported to be decreased in aged mice (18 mo) (Bach et al. 1999). In contrast, a brief 1-Hz paired-pulse stimulation has been found to induce an L-LTP in old mice but not in young animals (Huang and Kandel 2006). In our work, we focused on...

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“…It is widely known that postsynaptic [Ca 2+ ] i and L-type voltage-gated calcium channel currents are upregulated in the hippocampus during aging, despite a significant decrease of cell density [30] . Elevated postsynaptic [Ca 2+ ] i and L-type voltage-gated calcium channel activity contribute to impaired synaptic plasticity [31] and working memory [32] in aged hippocampal neurons. The increase of L-type voltage-gated calcium channel currents also enhances the susceptibility of aging neurons for apoptosis.…”

Section: Mechanism Of Action Of Ginsenoside Rb1 On the Vgccs In Hippomentioning

confidence: 99%

Ginsenoside Rb1 selectively inhibits the activity of L-type voltage-gated calcium channels in cultured rat hippocampal neurons

et al. 2012

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Age-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

Cited by 125 publications

References 55 publications

Increased phosphorylation of the neuronal L-type Ca ²⁺ channel Ca _v 1.2 during aging

Increased phosphorylation of the neuronal L-type Ca ²⁺ channel Ca _v 1.2 during aging

Synapse specificity of long-term potentiation breaks down with aging

Ginsenoside Rb1 selectively inhibits the activity of L-type voltage-gated calcium channels in cultured rat hippocampal neurons

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Age-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

Cited by 125 publications

References 55 publications

Increased phosphorylation of the neuronal L-type Ca 2+ channel Ca v 1.2 during aging

Increased phosphorylation of the neuronal L-type Ca 2+ channel Ca v 1.2 during aging

Synapse specificity of long-term potentiation breaks down with aging

Ginsenoside Rb1 selectively inhibits the activity of L-type voltage-gated calcium channels in cultured rat hippocampal neurons

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Increased phosphorylation of the neuronal L-type Ca ²⁺ channel Ca _v 1.2 during aging

Increased phosphorylation of the neuronal L-type Ca ²⁺ channel Ca _v 1.2 during aging