GluN2B but Not GluN2A for Basal Dendritic Growth of Cortical Pyramidal Neurons

Gonda, Steffen; Giesen, J; Sieberath, Alexander; West, Fabian; Buchholz, Raoul; Klatt, Oliver; Ziebarth, Tim; Räk, Andrea; Kleinhubbert, Sabine; Riedel, Christian; Hollmann, Michael; Hamad, Mohammad I. K.; Reiner, Andreas; Wahle, Petra

doi:10.3389/fnana.2020.571351

Cited by 17 publications

(19 citation statements)

References 83 publications

(131 reference statements)

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“…Our observations are consistent with previous studies demonstrating that basal dendrite arbors are specifically reduced by expression of ASD-associated mutations in Epac2 (Srivastava et al, 2012) and loss of the ASD-associated TAO2 (de Anda et al, 2012). Interestingly, it was recently shown that GluN2B antagonists preferentially reduced basal dendrite branch number without significantly changing apical dendrite branching in cortical pyramidal neurons in organotypic slices (Gonda et al, 2020).…”

Section: Discussionsupporting

confidence: 93%

An Autism-Associated de novo Mutation in GluN2B Destabilizes Growing Dendrites by Promoting Retraction and Pruning

Bahry

Fedder-Semmes

Sceniak

et al. 2021

Front. Cell. Neurosci.

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Mutations in GRIN2B, which encodes the GluN2B subunit of NMDA receptors, lead to autism spectrum disorders (ASD), but the pathophysiological mechanisms remain unclear. Recently, we showed that a GluN2B variant that is associated with severe ASD (GluN2B724t) impairs dendrite morphogenesis. To determine which aspects of dendrite growth are affected by GluN2B724t, we investigated the dynamics of dendrite growth and branching in rat neocortical neurons using time-lapse imaging. GluN2B724t expression shifted branch motility toward retraction and away from extension. GluN2B724t and wild-type neurons formed new branches at similar rates, but mutant neurons exhibited increased pruning of dendritic branches. The observed changes in dynamics resulted in nearly complete elimination of the net expansion of arbor size and complexity that is normally observed during this developmental period. These data demonstrate that ASD-associated mutant GluN2B interferes with dendrite morphogenesis by reducing rates of outgrowth while promoting retraction and subsequent pruning. Because mutant dendrites remain motile and capable of growth, it is possible that reducing pruning or promoting dendrite stabilization could overcome dendrite arbor defects associated with GRIN2B mutations.

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Section: Discussionsupporting

confidence: 93%

An Autism-Associated de novo Mutation in GluN2B Destabilizes Growing Dendrites by Promoting Retraction and Pruning

Bahry

Fedder-Semmes

Sceniak

et al. 2021

Front. Cell. Neurosci.

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“…Furthermore, surface expression of AMPARs was increased in a knock-in mouse model in which the wild-type GABA B R was replaced with a S783A-mutated version that cannot be phosphorylated (Terunuma et al, 2014). That NMDARs are not involved in reelin-mediated interneuron dendritic growth is expected, as recent data have shown that NMDARs do not affect the neocortical dendritic growth of interneurons (Gonda et al, 2020). During embryonic development, GABA is the main neurotransmitter, and it is not hyperpolarizing at this stage, as GABA B R lacks coupling between G proteins and potassium channels until the end of the first postnatal week (Fukuda et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

Reelin restricts dendritic growth of interneurons in the neocortex

et al. 2021

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Reelin is a large secreted glycoprotein that regulates neuronal migration, lamination and establishment of dendritic architecture in the embryonic brain. Reelin expression switches postnatally from Cajal-Retzius cells to interneurons. However, reelin function in interneuron development is still poorly understood. Here, we investigated the role of reelin in interneuron development in the postnatal neocortex. To preclude early cortical migration defects caused by reelin deficiency, we employed a conditional reelin knock-out (RelncKO) mouse to induce postnatal reelin deficiency. Induced reelin deficiency caused dendritic hypertrophy in distal dendritic segments of neuropeptide-Y positive (NPY+) and calretinin positive (Calr+) interneurons, and in proximal dendritic segments of parvalbumin positive (Parv+) interneurons. Chronic recombinant Reelin treatment rescued dendritic hypertrophy in Relncko interneurons. Moreover, we provide evidence that RelncKO interneuron hypertrophy is due to presynaptic GABABR dysfunction. Thus, GABABRs in RelncKO interneurons were unable to block N-type (Cav2.2) Ca2+ channels that control neurotransmitter release. Consequently, the excessive Ca2+ influx through AMPA receptors, but not NMDA receptors caused interneuron dendritic hypertrophy. These findings suggest that reelin acts as a “stop-growth-signal” for postnatal interneuron maturation.

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“…Also, type I transmembrane AMPA receptor regulatory proteins promote the dendritogenesis in immature pyramidal cells by enhanced trafficking of endogenous AMPA receptors (Hamad et al, 2014). GluN2B-containing NMDA receptors by contrast regulate differentiation of pyramidal cell basal dendrites (Wedzony et al, 2005;Gonda et al, 2020). Further, overexpressing the kainate receptor GluK2 increases dendritic complexity of pyramidal cell apical dendrites of cortical layers II/III (L2/3) (Jack et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Chemogenetic Silencing of Differentiating Cortical Neurons Impairs Dendritic and Axonal Growth

Gasterstädt

Schröder

Cronin

et al. 2022

Front. Cell. Neurosci.

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Electrical activity is considered a key driver for the neurochemical and morphological maturation of neurons and the formation of neuronal networks. Designer receptors exclusively activated by designer drugs (DREADDs) are tools for controlling neuronal activity at the single cell level by triggering specific G protein signaling. Our objective was to investigate if prolonged silencing of differentiating cortical neurons can influence dendritic and axonal maturation. The DREADD hM4Di couples to Gi/o signaling and evokes hyperpolarization via GIRK channels. HM4Di was biolistically transfected into neurons in organotypic slice cultures of rat visual cortex, and activated by clozapine-N-oxide (CNO) dissolved in H2O; controls expressed hM4Di, but were mock-stimulated with H2O. Neurons were analyzed after treatment for two postnatal time periods, DIV 5-10 and 10-20. We found that CNO treatment delays the maturation of apical dendrites of L2/3 pyramidal cells. Further, the number of collaterals arising from the main axon was significantly lower, as was the number of bouton terminaux along pyramidal cell and basket cell axons. The dendritic maturation of L5/6 pyramidal cells and of multipolar interneurons (basket cells and bitufted cells) was not altered by CNO treatment. Returning CNO-treated cultures to CNO-free medium for 7 days was sufficient to recover dendritic and axonal complexity. Our findings add to the view that activity is a key driver in particular of postnatal L2/3 pyramidal cell maturation. Our results further suggest that inhibitory G protein signaling may represent a factor balancing the strong driving force of neurotrophic factors, electrical activity and calcium signaling.

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GluN2B but Not GluN2A for Basal Dendritic Growth of Cortical Pyramidal Neurons

Cited by 17 publications

References 83 publications

An Autism-Associated de novo Mutation in GluN2B Destabilizes Growing Dendrites by Promoting Retraction and Pruning

An Autism-Associated de novo Mutation in GluN2B Destabilizes Growing Dendrites by Promoting Retraction and Pruning

Reelin restricts dendritic growth of interneurons in the neocortex

Chemogenetic Silencing of Differentiating Cortical Neurons Impairs Dendritic and Axonal Growth

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