Deletion of Neurotrophin Signaling through the Glucocorticoid Receptor Pathway Causes Tau Neuropathology

Arango-Lievano, Margarita; Peguet, Camille; Catteau, Matthias; Parmentier, Marie‐Laure; Wu, Synphen H.; Chao, Moses V.; Ginsberg, Stephen D.; Jeanneteau, Freddy

doi:10.1038/srep37231

Cited by 28 publications

(31 citation statements)

References 70 publications

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“…To ensure that BDNF-dependent GR-PO 4 effect on experience-dependent spine plasticity was cell autonomous in excitatory neurons of M1 cortex, we exclusively targeted this set of neurons by in utero electroporation (Figure S6A-C). Substitution of endogenous GR with the PO 4 -deficient GR mutant as previously described (30), decreased spine formation and increased spine elimination in the layer 1 of M1 cortex after the training that is consistent with a net decrease of spine density observed in the KI mice. This indicates that the effect of GR-PO 4 is cell-autonomous.…”

Section: Resultssupporting

confidence: 86%

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Persistence of learning-induced synapses depends on neurotrophic-priming of glucocorticoid receptors

Arango-Lievano

Borie

Dromard

et al. 2019

Preprint

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Stress can either promote or impair learning and memory. Such opposing effects depend on whether synapses persist or decay after learning. Maintenance of new synapses formed at the time of learning upon neuronal network activation depends on the stress hormone activated glucocorticoid receptor (GR) and neurotrophic factor release. Whether and how concurrent GR and neurotrophin signaling integrate to modulate synaptic plasticity and learning is unknown.Here we show that deletion of the neurotrophin BDNF-dependent GR phosphorylation sites (GR-PO 4 ) impairs long-term memory retention and maintenance of newly formed postsynaptic dendritic spines in the mouse cortex after motor skills training. Chronic stress and the BDNF polymorphism Val66Met disrupt the BDNF-dependent GR-PO 4 pathway necessary for preserving training-induced spines and previously acquired memories. Conversely, enrichment living promotes spine formation but fails to salvage training-related spines in mice lacking BDNF-dependent GR-PO 4 sites, suggesting it is essential for spine consolidation and memory retention. Mechanistically, spine maturation and persistence in the motor cortex depend on synaptic mobilization of the glutamate receptor GluA1 mediated by GR-PO 4 . Together, these findings indicate that regulation of GR-PO 4 via activity-dependent BDNF signaling is important for learning-dependent synapses formation and maintenance. They also define a new signaling mechanism underlying these effects. SIGNIFICANCE STATEMENTSignal transduction of receptors tyrosine kinase and nuclear receptors is essential for homeostasis. Phosphorylation is one of the currencies used by these receptors to support homeostatic reactions in learning and memory. Here we show that consolidation of learninginduced neuroplasticity is made possible via stress activated glucocorticoid nuclear receptor phosphorylation through the brain-derived neurotrophic tyrosine kinase pathway. Crosstalk between these pathways is specific of cell types and behavioral experience (e.g. learning, stress and enrichment living). Disruption of this response may contribute to the pathophysiology of stress-related disorders and treatment resistance. 3 \ b o d y

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Section: Resultssupporting

confidence: 86%

“…In vitro electroporations were performed with the AMAXA system. Plasmids electroporated consist of DNA vectors for molecular replacement of endogenous GR by the shRNA resistant PO 4 -deficient GR (GR-2A: S152A/S284A) or GR-WT as previously described (30).…”

Section: Methodsmentioning

confidence: 99%

Persistence of learning-induced synapses depends on neurotrophic-priming of glucocorticoid receptors

Arango-Lievano

Borie

Dromard

et al. 2019

Preprint

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“…A subcutaneous injection of the analgesic buprenorphine (Buprecare; 0.05 mg/kg) was administered postsurgery and the next day. The expression of transgenes in experimental animals generated by in utero electroporation was stable in adolescents but faded before reaching adulthood ( Arango-Lievano et al, 2016 ). Due to this technical reason, adolescent mice were used throughout the study.…”

Section: Methodsmentioning

confidence: 99%

The Stress-Induced Transcription Factor NR4A1 Adjusts Mitochondrial Function and Synapse Number in Prefrontal Cortex

et al. 2018

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The energetic costs of behavioral chronic stress are unlikely to be sustainable without neuronal plasticity. Mitochondria have the capacity to handle synaptic activity up to a limit before energetic depletion occurs. Protective mechanisms driven by the induction of neuronal genes likely evolved to buffer the consequences of chronic stress on excitatory neurons in prefrontal cortex (PFC), as this circuitry is vulnerable to excitotoxic insults. Little is known about the genes involved in mitochondrial adaptation to the buildup of chronic stress. Using combinations of genetic manipulations and stress for analyzing structural, transcriptional, mitochondrial, and behavioral outcomes, we characterized NR4A1 as a stress-inducible modifier of mitochondrial energetic competence and dendritic spine number in PFC. NR4A1 acted as a transcription factor for changing the expression of target genes previously involved in mitochondrial uncoupling, AMP-activated protein kinase activation, and synaptic growth. Maintenance of NR4A1 activity by chronic stress played a critical role in the regressive synaptic organization in PFC of mouse models of stress (male only). Knockdown, dominant-negative approach, and knockout of Nr4a1 in mice and rats (male only) protected pyramidal neurons against the adverse effects of chronic stress. In human PFC tissues of men and women, high levels of the transcriptionally active NR4A1 correlated with measures of synaptic loss and cognitive impairment. In the context of chronic stress, prolonged expression and activity of NR4A1 may lead to responses of mitochondria and synaptic connectivity that do not match environmental demand, resulting in circuit malfunction between PFC and other brain regions, constituting a pathological feature across disorders.SIGNIFICANCE STATEMENT The bioenergetic cost of chronic stress is too high to be sustainable by pyramidal prefrontal neurons. Cellular checkpoints have evolved to adjust the responses of mitochondria and synapses to the buildup of chronic stress. NR4A1 plays such a role by controlling the energetic competence of mitochondria with respect to synapse number. As an immediate-early gene, Nr4a1 promotes neuronal plasticity, but sustained expression or activity can be detrimental. NR4A1 expression and activity is sustained by chronic stress in animal models and in human studies of neuropathologies sensitive to the buildup of chronic stress. Therefore, antagonism of NR4A1 is a promising avenue for preventing the regressive synaptic reorganization in cortical systems in the context of chronic stress.

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“…This could explain differential modulation of GR activity in mesolimbic and corticolimbic networks. Deletion of GR phosphorylation sites in neurons belonging to corticolimbic brain areas interferes with the expression of GR-regulated target genes involved in cytoskeleton dynamics, mitochondrial functions, synapse formation and maintenance (62,68,69). What's more, BDNF-dependent GR phosphorylation sites reside near a caspase-1 site, whose cleavage causes partial loss of GR transcriptional activity in animal models and a disease of glucocorticoid resistance in humans (70,71).…”

Section: Effect Of Bdnf and Glucocorticoid Signaling In Health And DImentioning

confidence: 99%

Bridging the Gap between Brain-Derived Neurotrophic Factor and Glucocorticoid Effects on Brain Networks

et al. 2018

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Behavioral choices made by the brain during stress depend on glucocorticoid and BDNF signaling pathways acting in synchrony in the mesolimbic (reward) and corticolimbic (emotion) neural networks. Deregulated expression of BDNF and glucocorticoid receptors in brain valuation areas may compromise integration of signals. Glucocorticoid receptor phosphorylation upon BDNF signaling in neurons represents one mechanism underlying the integration of BDNF and glucocorticoid signals that when off balance may lay the foundation of maladaptations to stress.Here, we propose that BDNF signaling conditions glucocorticoid responses impacting neural plasticity in the mesocorticolimbic system. This provides a novel molecular framework for understanding how brain networks use BDNF and glucocorticoid signaling contingencies to forge receptive neuronal fields in temporal domains defined by behavioral experience, and in mood disorders. Introduction Cooperation between the mesolimbic and corticolimbic systems determines behavioral choicesBrain region-specific effects of BDNF and glucocorticoids on the mesocorticolimbic system Bridging the gaps between BDNF and glucocorticoid effects in the mesocorticolimbic system GR phosphorylation is influenced by BDNF signaling Effect of BDNF and glucocorticoid signaling in health and disease Summary References

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Deletion of Neurotrophin Signaling through the Glucocorticoid Receptor Pathway Causes Tau Neuropathology

Cited by 28 publications

References 70 publications

Persistence of learning-induced synapses depends on neurotrophic-priming of glucocorticoid receptors

Persistence of learning-induced synapses depends on neurotrophic-priming of glucocorticoid receptors

The Stress-Induced Transcription Factor NR4A1 Adjusts Mitochondrial Function and Synapse Number in Prefrontal Cortex

Bridging the Gap between Brain-Derived Neurotrophic Factor and Glucocorticoid Effects on Brain Networks

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