Roles for calcium signaling in structural plasticity and pathology in the hippocampal system

Mattson, Mark P.; Barger, Steven W.

doi:10.1002/hipo.1993.4500030711

Cited by 27 publications

(5 citation statements)

References 125 publications

(172 reference statements)

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“…Activated microglia can evoke neuronal cell death, but equally harmful effects on function could result from the loss of synaptic connectivity. Furthermore, glutamate has been documented to prune dendrites dosimetrically and chronologically prior to causing outright cell death (Mattson and Barger 1993). Therefore, we tested whether microglia activated by sublethal concentrations of sAPP could have this kind of subtle effect.…”

Section: Resultsmentioning

confidence: 99%

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Activation of microglia by secreted amyloid precursor protein evokes release of glutamate by cystine exchange and attenuates synaptic function

Barger

Basile

2001

Journal of Neurochemistry

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236

137

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Microglial activation as part of a chronic in¯ammatory response is a prominent component of Alzheimer's disease. Secreted forms of the b-amyloid precursor protein (sAPP) previously were found to activate microglia, elevating their neurotoxic potential. To explore neurotoxic mechanisms, we analyzed microglia-conditioned medium for agents that could activate glutamate receptors. Conditioned medium from primary rat microglia activated by sAPP caused a calcium elevation in hippocampal neurons, whereas medium from untreated microglia did not. This response was sensitive to the NMDA receptor antagonist, aminophosphonovaleric acid. Analysis of microglia-conditioned by HPLC revealed dramatically higher concentrations of glutamate in cultures exposed to sAPP. Indeed, the glutamate levels in sAPP-treated cultures were substantially higher than those in cultures treated with amyloid b-peptide. This sAPP-evoked glutamate release was completely blocked by inhibition of the cystine± glutamate antiporter by a-aminoadipate or use of cystine-free medium. Furthermore, a sublethal concentration of sAPP compromised synaptic density in microglia±neuron cocultures, as evidenced by neuronal connectivity assay. Finally, the neurotoxicity evoked by sAPP in microglia-neuron cocultures was attenuated by inhibitors of either the neuronal nitric oxide synthase (N G -propyl-L-arginine) or inducible nitric oxide synthase (1400 W). Together, these data indicate a scenario by which microglia activated by sAPP release excitotoxic levels of glutamate, probably as a consequence of autoprotective antioxidant glutathione production within the microglia, ultimately causing synaptic degeneration and neuronal death. Keywords: Alzheimer's disease, glutamate, microglia, nitric oxide, synapse, xc exchange. Accumulating evidence indicates that chronic neuroin¯ammatory processes play a signi®cant role in the pathogenesis of Alzheimer's disease (AD). Non-steroidal anti-in¯ammatory drugs decrease the risk of incidence and slow the progression of AD (Breitner 1996). Moreover, the neuritic plaques pathognomic for AD contain activated microglia (reviewed in Grif®n et al. 1998), as do those plaques that accumulate in b-amyloid precursor protein (bAPP) transgenic mice (Frautschy et al. 1998;Huang et al. 1999;Stalder et al. 1999). Several substances are produced by these activated microglia that are implicated in models of neurotoxicity: pro-in¯ammatory, neurotoxic cytokines (Shohami et al. 1994;Chao et al. 1995;Yeung et al. 1995

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Section: Resultsmentioning

confidence: 99%

“…The damage evoked by an excitotoxin such as glutamate can be limited to dendrites dosimetrically; higher concentrations evoke whole‐cell killing (Mattson and Barger 1993). Similarly, concentrations of sAPP can be reached that will cause neuronal death in neuron/microglia cocultures (Barger and Harmon 1997).…”

Section: Resultsmentioning

confidence: 99%

Activation of microglia by secreted amyloid precursor protein evokes release of glutamate by cystine exchange and attenuates synaptic function

Barger

Basile

2001

Journal of Neurochemistry

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236

137

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“…1996). Furthermore, altered Ca 2+ homeostasis has been implicated in various neurodegenerative diseases, and correlative evidence indicates that calbindin‐D 28k has a neuroprotective function (Mattson & Barger 1993). Further investigations on the mechanisms that link Q‐ and L‐type VGCC activation and calbindin‐D 28k expression will help our understanding of activity‐dependent mechanisms in the developing and adult CNS, and may allow the development of strategies for preventing neuronal death in degenerative disorders.…”

Section: Discussionmentioning

confidence: 99%

Q‐ and L‐type calcium channels control the development of calbindin phenotype in hippocampal pyramidal neurons in vitro

Boukhaddaoui

Sieso

Scamps

et al. 2000

Eur J of Neuroscience

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Cultured immature hippocampal neurons from embryonic 17-day-old rats were used to explore activity-dependent regulation of neuronal phenotype differentiation in the developing hippocampus. The calbindin-D28k phenotype of the pyramidal neurons appeared during the first 6 days in culture, and was expressed by 12% of the cells on day 6. Daily stimulation with 50 mM KCl during the first 5 days in vitro increased the number of calbindin-D28k-positive pyramidal neurons without affecting neuronal survival. This effect was prevented by buffering extracellular Ca2+. Omega-agatoxin-IVA-sensitive Q-type and nitrendipine-sensitive L-type voltage-gated Ca2+ channels (VGCCs) carried Ca2+ currents and Ca2+ influx in immature pyramidal neurons at somata level. Blockade of these channels inhibited calbindin-D28k phenotype induced by 50 mM KCl. Conversely, glutamate-activated Ca2+ channel antagonists did not affect the KCl-induced calbindin-D28k phenotype. Chronic blockade of Q- and/or L-type VGCCs downregulated the normal calbindin-D28k development of immature pyramidal neurons without affecting neuronal survival, the somatic area of pyramidal neurons or the number of GABAergic-positive (gamma-aminobutyric acid) interneurons. However, at later developmental stages, Q-type VGCCs lost their ability to control Ca2+ influx at somata level, and both Q- and L-type VGCCs failed to regulate calbindin-D28k phenotype. These results suggest that Q-type channels, which have been predominantly associated with neurotransmitter release in adult brain, transiently act in synergy with L-type VGCCs to direct early neuronal differentiation of hippocampal pyramidal neurons before the establishment of their synaptic circuits.

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“…Because excitatory amino acid receptors are restricted to synapses and dendrites, these subcellular compartments are preferentially vulnerable. Exposures that do not kill the entire cell could therefore result in a disastrous degree of dendritic pruning [336]. Thus, microglia-produced excitotoxins may lead to cognitive impairment that is not necessarily correlated with neuronal cell loss.…”

Section: Microgliamentioning

confidence: 99%

Inflammation and Alzheimer's disease

Akiyama

2000

Neurobiology of Aging

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2,775

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Roles for calcium signaling in structural plasticity and pathology in the hippocampal system

Cited by 27 publications

References 125 publications

Activation of microglia by secreted amyloid precursor protein evokes release of glutamate by cystine exchange and attenuates synaptic function

Activation of microglia by secreted amyloid precursor protein evokes release of glutamate by cystine exchange and attenuates synaptic function

Q‐ and L‐type calcium channels control the development of calbindin phenotype in hippocampal pyramidal neurons in vitro

Inflammation and Alzheimer's disease

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