The BDNF Val66Met Prodomain Disassembles Dendritic Spines Altering Fear Extinction Circuitry and Behavior

Giza, Joanna; Kim, Jihye; Meyer, Heidi C.; Anastasía, Agustín; Dincheva, Iva; Zheng, Crystal I.; Lopez, Katherine; Bains, Henrietta; Yang, Jie; Bracken, Clay; Liston, Conor; Jing, Dapeng; Hempstead, Barbara L.; Lee, Francis S.

doi:10.1016/j.neuron.2018.08.041

Cited by 30 publications

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“…It remains unclear what ligands drive p75 NTR signalling in cBF neurons, and whether p75 NTR acts to facilitate Trk receptor signalling as well as acting independently to facilitate synaptic pruning, driven by the developmental stage or expression levels of co-receptors. The current dogma would suggest that proneurotrophins, acting together with the sortilin/SorCS family of co-receptors, is likely to be responsible for the pruning of synapses and axons via p75 NTR (as has been recently reported for a developmentally transient, p75 NTR -positive, prefrontal cortex-projecting hippocampal neuronal population [140]). Although mice in which sortilin receptor members are conditionally knocked out in cBF neurons have not been analysed, sequestration of proNGF with specific antibodies causes mild impairment in cognitively taxing, distractor attention tasks without affecting baseline attention [141], suggestive of changes to cholinergic neurotransmission.…”

Section: Effects Of Loss Of P75 Ntr Expression On Behaviour and Synapmentioning

confidence: 86%

Regulation of cholinergic basal forebrain development, connectivity, and function by neurotrophin receptors

et al. 2019

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Cholinergic basal forebrain (cBF) neurons are defined by their expression of the p75 neurotrophin receptor (p75NTR) and tropomyosin-related kinase (Trk) neurotrophin receptors in addition to cholinergic markers. It is known that the neurotrophins, particularly nerve growth factor (NGF), mediate cholinergic neuronal development and maintenance. However, the role of neurotrophin signalling in regulating adult cBF function is less clear, although in dementia, trophic signalling is reduced and p75NTR mediates neurodegeneration of cBF neurons. Here we review the current understanding of how cBF neurons are regulated by neurotrophins which activate p75NTR and TrkA, B or C to influence the critical role that these neurons play in normal cortical function, particularly higher order cognition. Specifically, we describe the current evidence that neurotrophins regulate the development of basal forebrain neurons and their role in maintaining and modifying mature basal forebrain synaptic and cortical microcircuit connectivity. Understanding the role neurotrophin signalling plays in regulating the precision of cholinergic connectivity will contribute to the understanding of normal cognitive processes and will likely provide additional ideas for designing improved therapies for the treatment of neurological disease in which cholinergic dysfunction has been demonstrated.

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Section: Effects Of Loss Of P75 Ntr Expression On Behaviour and Synapmentioning

confidence: 86%

Regulation of cholinergic basal forebrain development, connectivity, and function by neurotrophin receptors

et al. 2019

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“…One likely explanation is that, in these latter mice, the removal of p75NTR protein occurs too late to affect the maturation of these parameters in the visual cortex, which have for the most part reached plateau by the first postnatal month (Chattopadhyaya et al, 2004;Kang et al, 2013;Picard et al, 2014). Because p75NTR expression differs among brain regions at the different ages (Holm et al, 2009;Giza et al, 2018), it would be interesting to investigate whether PV_Cre;p75NTR lox/lox conditional KO mice show altered cognitive functions implicating regions which mature later, such as the PFC (Giza et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…The temporal and cellular localization of p75NTR in cortical neurons has been an object of debate and discrepancy (Holm et al, 2009;Giza et al, 2018), likely due to low protein expression levels, especially in the adult brain, and suboptimal antibody sensitivity. To overcome these technical challenges, we used two novel experimental strategies.…”

Section: Cortical Pv Cells Express P75ntr During Development and In Tmentioning

confidence: 99%

“…The neurotrophin receptor p75NTR is a multifunctional receptor modulating several critical steps in nervous system development and function, from apoptosis to synaptic plasticity (Lin et al, 2015). In particular, it has been shown that p75NTR interaction with the precursor form of BDNF, proBDNF, or with the prodomain alone, induces growth cone collapse and dendritic spine remodeling in hippocampal excitatory neurons (Anastasia et al, 2013;Giza et al, 2018), and alterations in this process may lead to long-term cognitive dysfunctions (Giza et al, 2018). Because of the difficulty in pinpointing p75NTR localization in cortical tissue with temporal and single-cell resolution, whether and how p75NTR plays a role on cortical GABAergic circuit development are not clear.…”

Section: Introductionmentioning

confidence: 99%

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p75 Neurotrophin Receptor Activation Regulates the Timing of the Maturation of Cortical Parvalbumin Interneuron Connectivity and Promotes Juvenile-like Plasticity in Adult Visual Cortex

et al. 2019

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By virtue of their extensive axonal arborization and perisomatic synaptic targeting, cortical inhibitory parvalbumin (PV) cells strongly regulate principal cell output and plasticity and modulate experience-dependent refinement of cortical circuits during development. An interesting aspect of PV cell connectivity is its prolonged maturation time course, which is completed only by end of adolescence. The p75 neurotrophin receptor (p75NTR) regulates numerous cellular functions; however, its role on cortical circuit development and plasticity remains elusive, mainly because localizing p75NTR expression with cellular and temporal resolution has been challenging. By using RNAscope and a modified version of the proximity ligation assay, we found that p75NTR expression in PV cells decreases between the second and fourth postnatal week, at a time when PV cell synapse numbers increase dramatically. Conditional knockout of p75NTR in single PV neurons in vitro and in PV cell networks in vivo causes precocious formation of PV cell perisomatic innervation and perineural nets around PV cell somata, therefore suggesting that p75NTR expression modulates the timing of maturation of PV cell connectivity in the adolescent cortex. Remarkably, we found that PV cells still express p75NTR in adult mouse cortex of both sexes and that its activation is sufficient to destabilize PV cell connectivity and to restore cortical plasticity following monocular deprivation in vivo. Together, our results show that p75NTR activation dynamically regulates PV cell connectivity, and represent a novel tool to foster brain plasticity in adults.

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“…Interestingly, the Val66met polymorphism of BDNF positioned in the prodomain alters the reported structural conformation (Anastasia et al, 2013;Wang et al, 2018), subcellular sorting and transport (Arango-Lievano et al, 2015a;Zanin et al, 2017), as well as activities of the prodomain: (i) Met66 carriers impaired the expression of LTD (Mizui et al, 2015), (ii) Met66 carriers elicited growth cone collapse (Anastasia et al, 2013) and (iii) Met66 carriers promoted dendritic spine elimination (Giza et al, 2018) as opposed to its counterpart the val66 carriers that facilitated LTD with no effects on axonal growth cones or dendritic spine turnover.…”

Section: Ii3 the Prodomainmentioning

confidence: 99%

Neurotrophin and synaptogenesis

Jeanneteau

Arango-Lievano

Chao

2020

Synapse Development and Maturation

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Synaptogenesis is encoded by multiple genes that program the assembly of neural networks in the immature brain during development and later in life, in the experienced brain that must respond to changes of the external world and of proprioception. Processing of neural network activity cannot solely rely on the activity of established synapses as their plasticity can saturate. For this reason, synaptogenesis is reversible. Assembly and disassembly of synapses depend on the exchange of signals between the pre-and post-synaptic terminals. Synaptic trophic factors are paramount for neural network remodeling, homeostasis and survival because they are present in limited supply. Neurotrophins present the necessary attributes to operate as synaptic trophin. It is speculated that many diverse and pleiotropic actions of neurotrophins on the synapse depend on the sources of neurotrophin ligands, its modes of secretion and signaling, all influenced by their locations at the synapse. What information is encoded when synaptic neurotrophin signaling is retrograde or anterograde, paracrine or autocrine? Answers emerged from the characterization of the cells that secrete neurotrophins, the cells that respond to neurotrophins, the various modes of secretion, receptor-signaling pathways, and the temporal constraints imposed by synaptic transmission. Failure to communicate the appropriate synaptic trophic signals impairs neuronal networks maintenance and updated wiring.

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The BDNF Val66Met Prodomain Disassembles Dendritic Spines Altering Fear Extinction Circuitry and Behavior

Cited by 30 publications

References 0 publications

Regulation of cholinergic basal forebrain development, connectivity, and function by neurotrophin receptors

Regulation of cholinergic basal forebrain development, connectivity, and function by neurotrophin receptors

p75 Neurotrophin Receptor Activation Regulates the Timing of the Maturation of Cortical Parvalbumin Interneuron Connectivity and Promotes Juvenile-like Plasticity in Adult Visual Cortex

Neurotrophin and synaptogenesis

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