Cytoskeletal regulation of synaptogenesis in a model of human fetal brain development

Wilson, Emily S; Rudisill, Taylor; Kirk, Brenna; Johnson, Colin G.; Kemper, None Paige; Litwa, Karen

doi:10.1002/jnr.24692

Cited by 9 publications

(19 citation statements)

References 78 publications

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“…Distance from the pre-to post-synaptic marker ( Fig. 2G) is about 100 nm, consistent with our previous observations 48 . In contrast to studies of mature mammalian synapses, in which HA surrounds the synapse but is absent from the synaptic cleft 9,49 , this result suggests that during synapse formation, HA is uniquely positioned between pre-and post-synaptic compartments.…”

Section: Resultssupporting

confidence: 92%

“…Conversely, our observation that HA decreases excitatory synapse formation could have implications for aging and Alzheimer's Disease, both of which exhibit HA accumulation and synapse loss [69][70][71][72] . In particular, aging is associated with loss of synapses that form on highly plastic thin spines 69 , which resemble the filopodia-like spine precursors involved in prenatal synaptogenesis 30,48,73 . Thus, the findings in the study could have relevance for a spectrum of neurologic conditions, from neurodevelopmental disorders to agerelated cognitive decline.…”

Section: Discussionmentioning

confidence: 99%

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Hyaluronan regulates synapse formation and function in developing neural networks

Wilson

Knudson

Litwa

2020

Sci Rep

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Neurodevelopmental disorders present with synaptic alterations that disrupt the balance between excitatory and inhibitory signaling. For example, hyperexcitability of cortical neurons is associated with both epilepsy and autism spectrum disorders. However, the mechanisms that initially establish the balance between excitatory and inhibitory signaling in brain development are not well understood. Here, we sought to determine how the extracellular matrix directs synapse formation and regulates synaptic function in a model of human cortical brain development. The extracellular matrix, making up twenty percent of brain volume, is largely comprised of hyaluronan. Hyaluronan acts as both a scaffold of the extracellular matrix and a space-filling molecule. Hyaluronan is present from the onset of brain development, beginning with neural crest cell migration. Through acute perturbation of hyaluronan levels during synaptogenesis, we sought to determine how hyaluronan impacts the ratio of excitatory to inhibitory synapse formation and the resulting neural activity. We used 3-D cortical spheroids derived from human induced pluripotent stem cells to replicate this neurodevelopmental window. Our results demonstrate that hyaluronan preferentially surrounds nascent excitatory synapses. Removal of hyaluronan increases the expression of excitatory synapse markers and results in a corresponding increase in the formation of excitatory synapses, while also decreasing inhibitory synapse formation. This increased excitatory synapse formation elevates network activity, as demonstrated by microelectrode array analysis. In contrast, the addition of purified hyaluronan suppresses excitatory synapse formation. These results establish that the hyaluronan extracellular matrix surrounds developing excitatory synapses, where it critically regulates synapse formation and the resulting balance between excitatory to inhibitory signaling.

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Hyaluronan regulates synapse formation and function in developing neural networks

Wilson

Knudson

Litwa

2020

Sci Rep

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“…Ultimately, nascent branches are either stabilized or retracted and eliminated. Distinct molecular mechanisms underlie different aspects of dendrite growth (Vaillant et al, 2002;Baumert et al, 2020;Wilson et al, 2020). For example, glutamate-mediated signaling through mGluR5 receptors leads to Ckd5-mediated phosphorylation of delta-catenin.…”

Section: Introductionmentioning

confidence: 99%

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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“…Notably, fluoxetine has been shown to upregulate neuroplasticity genes independent of serotonin [ 31 ] and to alter neurite outgrowth in non-serotonergic neural cell lines, mammalian primary neurons, and invertebrate neurons [ 32 , 33 ] similar to other selective serotonin reuptake inhibitors [ 34 ]. We therefore began by treating human neural progenitor cells with increasing doses of fluoxetine during the first 24 h of neural differentiation, as we have previously done to determine effects on early stages of neural differentiation and neurite extension [ 35 , 36 ]. The doses were selected to capture the range of clinically relevant concentrations, as brain fluoxetine concentrations are often higher than blood plasma levels, and may reach up to 10 μg/mL [ 37 ], while blood plasma levels are often around 100 ng/mL or 0.1 μg/mL [ 38 ], the lowest dose used in the present study.…”

Section: Resultsmentioning

confidence: 99%

Effects of the Selective Serotonin Reuptake Inhibitor Fluoxetine on Developing Neural Circuits in a Model of the Human Fetal Cortex

Tate

Kirk

Tseng

et al. 2021

IJMS

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The developing prenatal brain is particularly susceptible to environmental disturbances. During prenatal brain development, synapses form between neurons, resulting in neural circuits that support complex cognitive functions. In utero exposure to environmental factors such as pharmaceuticals that alter the process of synapse formation increases the risk of neurodevelopmental abnormalities. However, there is a lack of research into how specific environmental factors directly impact the developing neural circuitry of the human brain. For example, selective serotonin reuptake inhibitors are commonly used throughout pregnancy to treat depression, yet their impact on the developing fetal brain remains unclear. Recently, human brain models have provided unprecedented access to the critical window of prenatal brain development. In the present study, we used human neurons and cortical spheroids to determine whether the selective serotonin reuptake inhibitor fluoxetine alters neurite and synapse formation and the development of spontaneous activity within neural circuits. We demonstrate that cortical spheroids express serotonin transporter, thus recapitulating the early developmental expression of serotonin transporter associated with cortical pyramidal neurons. Cortical spheroids also appropriately express serotonin receptors, such as synaptic 5-HT2A and glial 5-HT5A. To determine whether fluoxetine can affect developing neural circuits independent of serotonergic innervation from the dorsal and medial raphe nuclei, we treated cortical neurons and spheroids with fluoxetine. Fluoxetine alters neurite formation in a dose-dependent fashion. Intriguingly, in cortical spheroids, neither acute nor chronic fluoxetine significantly altered excitatory synapse formation. However, only acute, but not chronic fluoxetine exposure altered inhibitory synaptogenesis. Finally, fluoxetine reversibly suppresses neuronal activity in a dose-dependent manner. These results demonstrate that fluoxetine can acutely alter synaptic function in developing neural circuits, but the effects were not long-lasting. This work provides a foundation for future studies to combine serotonergic innervation with cortical spheroids and assess the contributions of fluoxetine-induced alterations in serotonin levels to brain development.

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Cytoskeletal regulation of synaptogenesis in a model of human fetal brain development

Cited by 9 publications

References 78 publications

Hyaluronan regulates synapse formation and function in developing neural networks

Hyaluronan regulates synapse formation and function in developing neural networks

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

Effects of the Selective Serotonin Reuptake Inhibitor Fluoxetine on Developing Neural Circuits in a Model of the Human Fetal Cortex

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