Molecular determinants for the strictly compartmentalized expression of kainate receptors in CA3 pyramidal cells

Fièvre, Sabine; Carta, Mario; Chamma, Ingrid; Labrousse, Virginie F; Thoumine, Olivier; Mulle, Christophe

doi:10.1038/ncomms12738

Cited by 19 publications

(35 citation statements)

References 65 publications

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“…Thus, they may take on new functions as the animal develops. Consistent with this, cadherins function in diverse processes including neural tube formation (Hirano and Takeichi, 2012), axon targeting (Duan et al, 2014; Kuwako et al, 2014; Osterhout et al, 2011; Poskanzer et al, 2003), synapse formation (Togashi et al, 2002; Williams et al, 2011), synapse pruning (Bian et al, 2015), and synapse function (Bozdagi et al, 2010; Fièvre et al, 2016; Jungling et al, 2006; Mendez et al, 2010; Tang et al, 1998; Vitureira et al, 2011). Moreover, there is an overwhelming focus on the study and function of the broadly expressed N-cadherin/cadherin-2 and β-catenin, an intracellular binding partner common to all classic cadherins.…”

Section: Discussionmentioning

confidence: 62%

“…Several studies indicate that differential matching of Type II cadherins provides an adhesive code driving specific synapse formation (Duan et al, 2014; Kuwako et al, 2014; Osterhout et al, 2011; Poskanzer et al, 2003; Redies and Takeichi, 1996; Suzuki et al, 1997; Williams et al, 2011). Moreover, cadherins localize at synapses and regulate many synaptic functions including synaptic vesicle clustering, dendritic spine stabilization, glutamate receptor recruitment, short-term plasticity, and long-term plasticity (Aiga et al, 2010; Bozdagi et al, 2010; Fièvre et al, 2016; Hirano and Takeichi, 2012; Jungling et al, 2006; Mendez et al, 2010; Saglietti et al, 2007a; Tang et al, 1998; Togashi et al, 2002; Vitureira et al, 2011). However, the majority of these functional studies only investigated the role of cadherin-2 (also known as N-cadherin).…”

Section: Introductionmentioning

confidence: 99%

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Heterophilic Type II Cadherins Are Required for High-Magnitude Synaptic Potentiation in the Hippocampus

Basu

Duan

Taylor

et al. 2017

Neuron

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Summary Hippocampal CA3 neurons form synapses with CA1 neurons in two layers, stratum oriens (SO) and stratum radiatum (SR). Each layer develops unique synaptic properties but molecular mechanisms that mediate these differences are unknown. Here, we show SO synapses normally have significantly more mushroom spines and higher magnitude long-term potentiation (LTP) than SR synapses. Further, we discovered these differences require the Type II classic cadherins, cadherins-6, 9, and 10. Though cadherins typically function via trans-cellular homophilic interactions, our results suggest presynaptic cadherin-9 binds postsynaptic cadherins-6 and 10 to regulate mushroom spine density and high magnitude LTP in the SO layer. Loss of these cadherins has no effect on the lower magnitude LTP typically observed in the SR layer, demonstrating that cadherins-6, 9, and 10 are gatekeepers for high magnitude LTP. Thus, Type II cadherins may uniquely contribute to the specificity and strength of synaptic changes associated with learning and memory.

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Section: Discussionmentioning

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Heterophilic Type II Cadherins Are Required for High-Magnitude Synaptic Potentiation in the Hippocampus

Basu

Duan

Taylor

et al. 2017

Neuron

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“…Previous results have shown that GluK2 expression is important for physiological surface expression of KCC2 and corresponding chloride transport in cortical neurons (Mahadevan et al, 2014 ; Pressey et al, 2017 ; Garand et al, 2019 ). To validate the role of GluK2 in regulating KCC2 in vivo , we used lentiviral shRNA (shRNA GluK2 -EGFP) for local silencing of GluK2 in WT mice CA3 pyramidal neurons, where endogenous GluK2 is strongly expressed in dendrites (Fièvre et al, 2016 ). Control animals were injected with lentivirus encoding for EGFP.…”

Section: Resultsmentioning

confidence: 99%

The Kainate Receptor Subunit GluK2 Interacts With KCC2 to Promote Maturation of Dendritic Spines

Kesaf

Khirug

Dinh

et al. 2020

Front. Cell. Neurosci.

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Kainate receptors (KAR) play a crucial role in the plasticity and functional maturation of glutamatergic synapses. However, how they regulate structural plasticity of dendritic spines is not known. The GluK2 subunit was recently shown to coexist in a functional complex with the neuronal K-Cl cotransporter KCC2. Apart from having a crucial role in the maturation of GABAergic transmission, KCC2 has a morphogenic role in the maturation of dendritic spines. Here, we show that in vivo local inactivation of GluK2 expression in CA3 hippocampal neurons induces altered morphology of dendritic spines and reduction in mEPSC frequency. GluK2 deficiency also resulted in a strong change in the subcellular distribution of KCC2 as well as a smaller somatodendritic gradient in the reversal potential of GABA A. Strikingly, the aberrant morphology of dendritic spines in GluK2-deficient CA3 pyramidal neurons was restored by overexpression of KCC2. GluK2 silencing in hippocampal neurons significantly reduced the expression of 4.1N and functional form of the actin filament severing protein cofilin. Consistently, assessment of actin dynamics using fluorescence recovery after photobleaching (FRAP) of β-actin showed a significant increase in the stability of F-actin filaments in dendritic spines. In conclusion, our results demonstrate that GluK2-KCC2 interaction plays an important role in the structural maturation of dendritic spines. This also provides novel insights into the connection between KAR dysfunction, structural plasticity, and developmental disorders.

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“…In postnatal, excitatory synapses, N-cadherin is required for LTP and spine enlargement—but not LTD or spine density and morphology, suggesting that cadherins selectively regulate synapse plasticity (Bozdagi et al, 2010). Indeed, cadherin accumulation on synaptic membranes is required for stabilizing postsynaptic receptors, e.g., kainate receptors (Fièvre et al, 2016) and AMPAR (Mills et al, 2017). Catenins also regulate synapses: upon NMDAR activation, β-catenin is redistributed from the dendrite shaft to the spines (where it binds N-cadherin), leading to synapse enlargement, consistent with its role in learning and memory (Murase et al, 2002).…”

Section: Cell Adhesion Molecules Initiate Specify and Regulate Synapsesmentioning

confidence: 99%

The Emerging Role of Mechanics in Synapse Formation and Plasticity

Kilinc

2018

Front. Cell. Neurosci.

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The regulation of synaptic strength forms the basis of learning and memory, and is a key factor in understanding neuropathological processes that lead to cognitive decline and dementia. While the mechanical aspects of neuronal development, particularly during axon growth and guidance, have been extensively studied, relatively little is known about the mechanical aspects of synapse formation and plasticity. It is established that a filamentous actin network with complex spatiotemporal behavior controls the dendritic spine shape and size, which is thought to be crucial for activity-dependent synapse plasticity. Accordingly, a number of actin binding proteins have been identified as regulators of synapse plasticity. On the other hand, a number of cell adhesion molecules (CAMs) are found in synapses, some of which form transsynaptic bonds to align the presynaptic active zone (PAZ) with the postsynaptic density (PSD). Considering that these CAMs are key components of cellular mechanotransduction, two critical questions emerge: (i) are synapses mechanically regulated? and (ii) does disrupting the transsynaptic force balance lead to (or exacerbate) synaptic failure? In this mini review article, I will highlight the mechanical aspects of synaptic structures—focusing mainly on cytoskeletal dynamics and CAMs—and discuss potential mechanoregulation of synapses and its relevance to neurodegenerative diseases.

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Molecular determinants for the strictly compartmentalized expression of kainate receptors in CA3 pyramidal cells

Cited by 19 publications

References 65 publications

Heterophilic Type II Cadherins Are Required for High-Magnitude Synaptic Potentiation in the Hippocampus

Heterophilic Type II Cadherins Are Required for High-Magnitude Synaptic Potentiation in the Hippocampus

The Kainate Receptor Subunit GluK2 Interacts With KCC2 to Promote Maturation of Dendritic Spines

The Emerging Role of Mechanics in Synapse Formation and Plasticity

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