LTP-triggered cholesterol redistribution activates Cdc42 and drives AMPA receptor synaptic delivery

Brachet, Anna; Norwood, Stephanie; Brouwers, Jos F.; Palomer, Ernest; Helms, J. Bernd; Dotti, Carlos G.; Esteban, José A.

doi:10.1085/jgp.1454oia11

Cited by 14 publications

(22 citation statements)

References 59 publications

(71 reference statements)

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“…Associative learning and memory in the contextual fear conditioning test was also impaired in the NPC1 nmf164 mice compared to wt mice, as evidenced by a 62% reduction in freezing time ( Fig 3H). Mutant NPC1 fails to support cholesterol redistribution and CYP46A1 and AMPA receptor surface delivery during LTP Recent evidence has shown that LTP-triggered cholesterol redistribution and reduction is necessary for the synaptic delivery of AMPA receptors [18], which in turn allows LTP progression. Mutant NPC1 fails to support cholesterol redistribution and CYP46A1 and AMPA receptor surface delivery during LTP Recent evidence has shown that LTP-triggered cholesterol redistribution and reduction is necessary for the synaptic delivery of AMPA receptors [18], which in turn allows LTP progression.…”

Section: Altered Synaptic Function and Behaviour In Npc1 Nmf164 Micementioning

confidence: 99%

“…Mutant NPC1 fails to support cholesterol redistribution and CYP46A1 and AMPA receptor surface delivery during LTP Recent evidence has shown that LTP-triggered cholesterol redistribution and reduction is necessary for the synaptic delivery of AMPA receptors [18], which in turn allows LTP progression. In agreement with the results reported by Brachet et al [18], cLTP induced a 30.4% reduction of cholesterol in the plasma membrane-enriched fraction of wt slices. To maximize the number of synapses undergoing plasticity, cLTP was pharmacologically induced, resulting in synapse activation similar to physiological LTP [29][30][31].…”

Section: Altered Synaptic Function and Behaviour In Npc1 Nmf164 Micementioning

confidence: 99%

“…Mobilization of the ER protein cholesterol hydroxylase CYP46A1 to the plasma membrane occurs upon excitatory stimulus by unknown means [21] and drives cholesterol reduction in LTP [18]. It has been proposed that an ER-derived carrier interacts with the plasma membrane allowing CYP46A1 to be exposed to the outside of the cell, thus releasing hydroxylated cholesterol.…”

Section: Altered Synaptic Function and Behaviour In Npc1 Nmf164 Micementioning

confidence: 99%

“…Lipid dynamics is a major determinant for the synaptic plasticity instrumental for learning and memory [17]. Activation of NMDA glutamate receptors during LTP, which is considered to be the molecular paradigm of memory, triggers cholesterol redistribution and reduction that drive postsynaptic delivery of AMPA receptors in hippocampal neurons [18].…”

Section: Introductionmentioning

confidence: 99%

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NPC 1 enables cholesterol mobilization during long‐term potentiation that can be restored in Niemann–Pick disease type C by CYP 46A1 activation

et al. 2019

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NPC is a neurodegenerative disorder characterized by cholesterol accumulation in endolysosomal compartments. It is caused by mutations in the gene encoding NPC1, an endolysosomal protein mediating intracellular cholesterol trafficking. Cognitive and psychiatric alterations are hallmarks in NPC patients pointing to synaptic defects. However, the role of NPC1 in synapses has not been explored. We show that NPC1 is present in the postsynaptic compartment and is locally translated during LTP. A mutation in a region of the NPC1 gene commonly altered in NPC patients reduces NPC1 levels at synapses due to enhanced NPC1 protein degradation. This leads to shorter postsynaptic densities, increased synaptic cholesterol and impaired LTP in NPC1nmf164 mice with cognitive deficits. NPC1 mediates cholesterol mobilization and enables surface delivery of CYP46A1 and GluA1 receptors necessary for LTP, which is defective in NPC1nmf164 mice. Pharmacological activation of CYP46A1 normalizes synaptic levels of cholesterol, LTP and cognitive abilities, and extends life span of NPC1nmf164 mice. Our results unveil NPC1 as a regulator of cholesterol dynamics in synapses contributing to synaptic plasticity, and provide a potential therapeutic strategy for NPC patients.

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Section: Altered Synaptic Function and Behaviour In Npc1 Nmf164 Micementioning

confidence: 99%

Section: Altered Synaptic Function and Behaviour In Npc1 Nmf164 Micementioning

confidence: 99%

Section: Altered Synaptic Function and Behaviour In Npc1 Nmf164 Micementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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NPC 1 enables cholesterol mobilization during long‐term potentiation that can be restored in Niemann–Pick disease type C by CYP 46A1 activation

et al. 2019

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“…45,46 In the case of Rab11, it is widely accepted that its association with recycling endosomes facilitates the delivery of previously endocytosed AMPARs back to the synaptic membrane, 44 interacting with myosin Vb and the endosomal adaptor Rab11-FIP2 upon glycine-induced LTP. 43 Accordingly, dominant-negative Rab11 inhibits the elevation in synaptic AMPARs induced by cholesterol depletion or during chemically induced LTP, 44,56 depletes mobile AMPARs at synapses 57 and blocks LTP formation. 28,44 Interestingly, overexpression of wild-type Rab11 leads to robust glycine-induced AMPAR insertion 44 while short-term removal or addition of Rab11 recycling endosomes from spines does not impair spine expansion during chemically induced LTP in hippocampal neurons.…”

Section: Rab Proteins Regulating Ampar Trafficking Under Ltpmentioning

confidence: 99%

Coordination of AMPA receptor trafficking by Rab GTPases

Haußer

Schlett

2017

Small GTPases

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Synaptic connections in the brain are continuously weakened or strengthened in response to changes in neuronal activity. This process, known as synaptic plasticity, is the cellular basis for learning and memory, and is thought to be altered in several neuronal disorders. An important aspect of synaptic plasticity is the tightly controlled trafficking and synaptic targeting of the AMPAtype glutamate receptors, which are the major mediators of fast excitatory transmission in the brain. This review addresses the role of Rab GTPases in AMPA receptor trafficking in neurons under basal conditions and during activity-induced synaptic plasticity, especially during long-term potentiation (LTP) and long-term depression (LTD). We highlight the importance of the tight spatio-temporal control of Rab activity and suggest that this is critical for proper neuronal functions. We also discuss how abnormal AMPA receptor trafficking and malfunctioning of Rabs can lead to neurologic disorders or memory problems.

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Perinatal exposure to pesticides alters synaptic plasticity signaling and induces behavioral deficits associated with neurodevelopmental disorders

et al. 2022

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Increasing evidence from animal and epidemiological studies indicates that perinatal exposure to pesticides cause developmental neurotoxicity and may increase the risk for psychiatric disorders such as autism and intellectual disability. However, the underlying pathogenic mechanisms remain largely elusive. This work was aimed at testing the hypothesis that developmental exposure to different classes of pesticides hijacks intracellular neuronal signaling contributing to synaptic and behavioral alterations associated with neurodevelopmental disorders (NDD). Low concentrations of organochlorine (dieldrin, endosulfan, and chlordane) and organophosphate (chlorpyrifos and its oxon metabolite) pesticides were chronically dosed ex vivo (organotypic rat hippocampal slices) or in vivo (perinatal exposure in rats), and then biochemical, electrophysiological, behavioral, and proteomic studies were performed. All the pesticides tested caused prolonged activation of MAPK/ERK pathway in a concentration-dependent manner. Additionally, some of them impaired metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD). In the case of the pesticide chlordane, the effect was attributed to chronic modulation of MAPK/ERK signaling. These synaptic alterations were reproduced following developmental in vivo exposure to chlordane and chlorpyrifos-oxon, and were also associated with prototypical behavioral phenotypes of NDD, including impaired motor development, increased anxiety, and social and memory deficits. Lastly, proteomic analysis revealed that these pesticides differentially regulate the expression of proteins in the hippocampus with pivotal roles in brain development and synaptic signaling, some of which are associated with NDD. Based on these results, we propose a novel mechanism of synaptic dysfunction, involving chronic overactivation of MAPK and impaired mGluR-LTD, shared by different pesticides which may have important implications for NDD. Graphical abstract

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LTP-triggered cholesterol redistribution activates Cdc42 and drives AMPA receptor synaptic delivery

Cited by 14 publications

References 59 publications

NPC 1 enables cholesterol mobilization during long‐term potentiation that can be restored in Niemann–Pick disease type C by CYP 46A1 activation

NPC 1 enables cholesterol mobilization during long‐term potentiation that can be restored in Niemann–Pick disease type C by CYP 46A1 activation

Coordination of AMPA receptor trafficking by Rab GTPases

Perinatal exposure to pesticides alters synaptic plasticity signaling and induces behavioral deficits associated with neurodevelopmental disorders

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