Thapsigargin blocks the induction of long-term potentiation in rat hippocampal slices

doi:10.1016/0304-3940(92)90551-H

Neuroscience Letters

Volume 139, Issue 2, 25 May 1992, Pages 197-200

https://doi.org/10.1016/0304-3940(92)90551-H Get rights and content

Abstract

Experiments were performed to investigate whether intact intracellular Ca²⁺ pools are necessary for long-term potentiation (LTP) in the CA1 region of rat hippocampal slices. Thapsigargin (1 μM), which depletes most intracellular Ca²⁺ pools by blocking ATP-dependent Ca²⁺ uptake into intracellular compartments, blocked the induction but not the expression of LTP. Thapsigargin had no effect on synaptic transmission or on responses mediated by $N- methyl- d -aspartate$ (NMDA) receptor activation. These data suggest that Ca²⁺ release from intracellular stores is required for the induction of LTP.

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Similar to NMDA receptor hypofunction and impaired synaptic plasticity, an increase in the AHP is an early marker of impaired hippocampal-dependent learning [151]. In young animals, Ca2+ from ICS facilitates induction of LTP [152,153]; however, during aging an increase in the AHP combined with NMDA receptor hypofunction raises the threshold for LTP induction in aged animals [150]. Indeed, the LTP impairment in aged animals can be ameliorated by treatments that reduce the AHP, permitting depolarization needed to activate NMDA receptors [65,71,150].
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LTP is an activity-dependent strengthening of synaptic transmission thought to underlie learning and memory. At excitatory synapses in hippocampal CA1, the Ca2+ required for the induction of LTP can be liberated from internal stores gated by IP3Rs (Harvey & Collingridge, 1992; Obenaus, Mody, & Baimbridge, 1989), and activation of group 1 mGlu receptors is a major trigger of this release (Frenguelli, Potier, Slater, Alford, & Collingridge, 1993; Petrozzino & Connor, 1994). Indeed, blockade or genetic deletion of group I mGlu receptors inhibits LTP at these synapses (Bashir, Bortolotto, et al., 1993), and disrupts hippocampus-dependent learning (Aiba et al., 1994; Balschun et al., 1999).
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Both LTP and LTD require an increase in the calcium concentration from extra- and/or intra-cellular sources. Calcium elevation is generally attributed to the activation of NMDAR and/or mGluR-mediated Ca2+ mobilization from intracellular stores through different signaling mechanisms (Bashir et al., 1993; Harvey and Collingridge, 1992; Malenka and Bear, 2004). NMDAR signalings can lead to Ca2+ influx by direct ion channel opening, whereas mGluR signaling can cause Ca2+ influx by indirect ion channel opening and/or by second messenger signaling systems.
Arsenic (As) is a neurotoxin induces dysfunction of learning and memory. Research has indicated that cerebellum may be involved in arsenic-induced impairment of learning and memory. However, the molecular mechanisms that underlie these effects remain unclear. This study screened for the differentially expressed genes related to the long-term potentiation and long-term depression (LTP and LTD) at the cerebellar postsynaptic density (PSD) of mice following exposure to arsenic, and we provide evidence of the mechanism by which arsenic adversely affects the functions of learning and memory. Here, SPF mice were exposed to 1 ppm, 2 ppm and 4 ppm As₂O₃ for 60 days. The ultrastructure of the synapses in cerebella of these mice was observed via transmission electron microscopy. The cerebellum global gene expression of mice exposed to 4 ppm As₂O₃ was determined through GeneChip analysis. We used the web tool DAVID to analyze the Gene Ontology (GO) and KEGG pathways that were signiﬁcantly enriched among the differentially expressed genes. Our observations of synaptic ultrastructure showed that the thickness of the cerebellar PSD was reduced in mice exposed to arsenic. Go analysis revealed the PSD as a significantly altered cellular component. KEGG pathway analysis showed that LTP and LTD were affected by arsenic with highest statistical significance, and 20 differentially expressed genes were associated with them. Among these differentially expressed genes, significant decreases in the mRNA expressions of CaMKII, Gria1, Gria2, Grin1, Itpr1, Grm1 and PLCβ4 related to the LTP and LTD were found at the PSD of mouse cerebellum exposed to arsenic. The downregulation of these genes was further confirmed via real-time reverse transcription PCR or Western blot at 1 ppm, 2 ppm and 4 ppm As₂O₃. Our results indicate that the 7 genes with in cerebellar PSDs may be involved in arsenic-induced neurotoxicity, including impairment of learning and memory.
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Long-term potentiation (LTP) of synaptic strength is a long-lasting form of synaptic plasticity that has been linked to information storage. Although the molecular and cellular events underlying LTP are not yet fully understood, it is generally accepted that changes in dendritic spine calcium levels as well as local protein synthesis play a central role. These two processes may be influenced by the presence of a spine apparatus, a distinct neuronal organelle found in a subpopulation of telencephalic spines. Mice lacking spine apparatuses (synaptopodin-deficient mice) show deficits in LTP and impaired spatial learning supporting the involvement of the spine apparatus in synaptic plasticity. In our review, we consider the possible roles of the spine apparatus in LTP1 (protein synthesis-independent), LTP2 (translation-dependent and transcription-independent) and LTP3 (translation- and transcription-dependent) and discuss the effects of the spine apparatus on learning and memory.
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Thapsigargin blocks the induction of long-term potentiation in rat hippocampal slices

Abstract

Neurosci. Lett.

Neuroscience

Dendritic Ca2+ transients associated with NMDA receptor-mediated synaptic currents in rat hippocampal slices

J. Physiol.

The role of divalent cations in the N-methyl-d-aspartate response of mouse central neurones in culture

J. Physiol.

A quantitative study of the actions of excitatory amino acids and antagonists in rat hippocampal slices

Br. J. Pharmacol.

Long-term potentiation of synaptic transmission in the hippocampus - properties and mechanisms

Neurol. Neurobiol.

Excitatory amino acids in synaptic transmission in the Schaffer collateral commissural pathway of the rat hippocampus

J. Physiol.

Dendritic Ca²⁺ transients associated with NMDA receptor-mediated synaptic currents in rat hippocampal slices

The role of divalent cations in the $N- methyl- d -aspartate$ response of mouse central neurones in culture