AMPA receptor trafficking pathways and links to dendritic spine morphogenesis

Hanley, Jonathan G.

doi:10.4161/cam.2.4.6510

Cited by 40 publications

(36 citation statements)

References 67 publications

(85 reference statements)

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“…Amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptors (AMPARs) play a central role in the modulation of excitatory synaptic transmission in the central nervous system (CNS) (Guntupalli, Widagdo & Anggono, 2016; Hanley, 2008; Hsieh et al., 2006). AMPARs are composed of four different subunits (glutamate receptor subunits A1 to A4), which regulate distinct functional aspects of the receptors (Hanley, 2008; Shepherd & Huganir, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…AMPARs are composed of four different subunits (glutamate receptor subunits A1 to A4), which regulate distinct functional aspects of the receptors (Hanley, 2008; Shepherd & Huganir, 2007). For example, subunits with long intracellular carboxy termini are involved in activity‐dependent synaptic targeting of AMPARs (GluA1, GluA2L, and GluA4), whereas those with a short intracellular carboxy end maintain basal synaptic neurotransmission (GluA2, GluA3, and GluA4s) (Hanley, 2008; Shepherd & Huganir, 2007). The role of the GluA1 subunit in learning and memory processes has been the most extensively investigated (Guntupalli et al., 2016; Hanley, 2008; Hsieh et al., 2006).…”

Section: Introductionmentioning

confidence: 99%

“…For example, subunits with long intracellular carboxy termini are involved in activity‐dependent synaptic targeting of AMPARs (GluA1, GluA2L, and GluA4), whereas those with a short intracellular carboxy end maintain basal synaptic neurotransmission (GluA2, GluA3, and GluA4s) (Hanley, 2008; Shepherd & Huganir, 2007). The role of the GluA1 subunit in learning and memory processes has been the most extensively investigated (Guntupalli et al., 2016; Hanley, 2008; Hsieh et al., 2006). The GluA1 subunit has several phosphorylation sites on its intracellular carboxy terminus (including Ser818, Ser831, and Ser845), and many of these sites are involved in the regulation of AMPARs at the synapse (Olivito et al., 2016).…”

Section: Introductionmentioning

confidence: 99%

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Impaired AMPA signaling and cytoskeletal alterations induce early synaptic dysfunction in a mouse model of Alzheimer's disease

et al. 2018

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SummaryAlzheimer's disease (AD) is a devastating neurodegenerative disorder that impairs memory and causes cognitive and psychiatric deficits. New evidences indicate that AD is conceptualized as a disease of synaptic failure, although the molecular and cellular mechanisms underlying these defects remain to be elucidated. Determining the timing and nature of the early synaptic deficits is critical for understanding the progression of the disease and for identifying effective targets for therapeutic intervention. Using single‐synapse functional and morphological analyses, we find that AMPA signaling, which mediates fast glutamatergic synaptic transmission in the central nervous system (CNS), is compromised early in the disease course in an AD mouse model. The decline in AMPA signaling is associated with changes in actin cytoskeleton integrity, which alters the number and the structure of dendritic spines. AMPA dysfunction and spine alteration correlate with the presence of soluble but not insoluble Aβ and tau species. In particular, we demonstrate that these synaptic impairments can be mitigated by Aβ immunotherapy. Together, our data suggest that alterations in AMPA signaling and cytoskeletal processes occur early in AD. Most important, these deficits are prevented by Aβ immunotherapy, suggesting that existing therapies, if administered earlier, could confer functional benefits.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Impaired AMPA signaling and cytoskeletal alterations induce early synaptic dysfunction in a mouse model of Alzheimer's disease

et al. 2018

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“…Structural plasticity of spines occurs alongside plasticity of synaptic transmission, requires modifications to the underlying actin cytoskeleton and is regulated by specific kinds of synaptic activity, most notably NMDA receptor (NMDAR) stimulation (Kasai et al , 2010; Bosch & Hayashi, 2012; Fortin et al , 2012). Long‐term potentiation (LTP) is an increase in synaptic strength caused by up‐regulating synaptic AMPA receptors (AMPARs) and involves an increase in spine size, whereas long‐term depression (LTD) is a decrease in synaptic strength caused by the internalisation of synaptic AMPARs and associated spine shrinkage (Hanley, 2008; Anggono & Huganir, 2012; Fortin et al , 2012). Long‐term plasticity of dendritic spines is thought to be an important cellular mechanism for information storage in the brain and therefore to play an essential role in learning and memory and the fine‐tuning of neural circuitry during development (Kasai et al , 2010; Caroni et al , 2012).…”

Section: Introductionmentioning

confidence: 99%

NMDAR ‐dependent Argonaute 2 phosphorylation regulates mi RNA activity and dendritic spine plasticity

et al. 2018

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MicroRNAs (miRNAs) repress translation of target mRNAs by associating with Argonaute (Ago) proteins to form the RNA‐induced silencing complex (RISC), underpinning a powerful mechanism for fine‐tuning protein expression. Specific miRNAs are required for NMDA receptor (NMDAR)‐dependent synaptic plasticity by modulating the translation of proteins involved in dendritic spine morphogenesis or synaptic transmission. However, it is unknown how NMDAR stimulation stimulates RISC activity to rapidly repress translation of synaptic proteins. We show that NMDAR stimulation transiently increases Akt‐dependent phosphorylation of Ago2 at S387, which causes an increase in binding to GW182 and a rapid increase in translational repression of LIMK1 via miR‐134. Furthermore, NMDAR‐dependent down‐regulation of endogenous LIMK1 translation in dendrites and dendritic spine shrinkage requires phospho‐regulation of Ago2 at S387. AMPAR trafficking and hippocampal LTD do not involve S387 phosphorylation, defining this mechanism as a specific pathway for structural plasticity. This work defines a novel mechanism for the rapid transduction of NMDAR stimulation into miRNA‐mediated translational repression to control dendritic spine morphology.

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“…Structural and functional modifications of synapses rely on activity-dependent remodeling of the actin cytoskeleton (Lamprecht and LeDoux 2004;Dillon and Goda 2005;Hanley 2008). Importantly, this process is integral to LTM formation across various brain regions including those regions essential for associative learning (Fischer et al 2004;Mantzur et al 2009).…”

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confidence: 99%

Myosin II motor activity in the lateral amygdala is required for fear memory consolidation

Gavin¹,

Rubio²,

Young³

et al. 2011

Learn. Mem.

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Learning induces dynamic changes to the actin cytoskeleton that are required to support memory formation. However, the molecular mechanisms that mediate filamentous actin (F-actin) dynamics during learning and memory are poorly understood. Myosin II motors are highly expressed in actin-rich growth structures including dendritic spines, and we have recently shown that these molecular machines mobilize F-actin in response to synaptic stimulation and learning in the hippocampus. In this study, we report that Myosin II motors in the rat lateral amygdala (LA) are essential for fear memory formation. Pretraining infusions of the Myosin II inhibitor, blebbistatin (blebb), disrupted long term memory, while short term memory was unaffected. Interestingly, both post-training and pretesting infusions had no effect on memory formation, indicating that Myosin II motors operate during or shortly after learning to promote memory consolidation. These data support the idea that Myosin II motor-force generation is a general mechanism that supports memory consolidation in the mammalian CNS.

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AMPA receptor trafficking pathways and links to dendritic spine morphogenesis

Cited by 40 publications

References 67 publications

Impaired AMPA signaling and cytoskeletal alterations induce early synaptic dysfunction in a mouse model of Alzheimer's disease

Impaired AMPA signaling and cytoskeletal alterations induce early synaptic dysfunction in a mouse model of Alzheimer's disease

NMDAR ‐dependent Argonaute 2 phosphorylation regulates mi RNA activity and dendritic spine plasticity

Myosin II motor activity in the lateral amygdala is required for fear memory consolidation

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