Article

Kwon HB, Sabatini BL. Glutamate induces de novo growth of functional spines in developing cortex. Nature 474: 100-104

Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature (Impact Factor: 41.46). 06/2011; 474(7349):100-4. DOI: 10.1038/nature09986
Source: PubMed

ABSTRACT

Mature cortical pyramidal neurons receive excitatory inputs onto small protrusions emanating from their dendrites called spines. Spines undergo activity-dependent remodelling, stabilization and pruning during development, and similar structural changes can be triggered by learning and changes in sensory experiences. However, the biochemical triggers and mechanisms of de novo spine formation in the developing brain and the functional significance of new spines to neuronal connectivity are largely unknown. Here we develop an approach to induce and monitor de novo spine formation in real time using combined two-photon laser-scanning microscopy and two-photon laser uncaging of glutamate. Our data demonstrate that, in mouse cortical layer 2/3 pyramidal neurons, glutamate is sufficient to trigger de novo spine growth from the dendrite shaft in a location-specific manner. We find that glutamate-induced spinogenesis requires opening of NMDARs (N-methyl-D-aspartate-type glutamate receptors) and activation of protein kinase A (PKA) but is independent of calcium-calmodulin-dependent kinase II (CaMKII) and tyrosine kinase receptor B (TrkB) receptors. Furthermore, newly formed spines express glutamate receptors and are rapidly functional such that they transduce presynaptic activity into postsynaptic signals. Together, our data demonstrate that early neural connectivity is shaped by activity in a spatially precise manner and that nascent dendrite spines are rapidly functionally incorporated into cortical circuits.

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    • "As a control for non-specific, photodamage-induced changes in tissue fluorescence, in a subset of trials, an interleaved stimulus of identical strength was delivered to a control site >5 mm away from any labeled dendrite (Figure 2B, Figure 2—figure supplement 1) (0.5 vs. 0 success probability at proximal and distal uncaging locations; 82 trials from 2 mice). As was previously described for layer 2/3 pyramidal neurons, P8-13 SPNs of both pathways were capable of de novo spinogenesis in response to glutamate uncaging (Kozorovitskiy et al., 2012; Kwon and Sabatini, 2011). The basal rate of spinogenesis (the probability of induction of a structure shaped like a dendritic spine), as well as its dependence on uncaging pulse width and proximity to "
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    ABSTRACT: Dopamine is released in striatum during development and impacts the activity of Protein Kinase A (PKA) in striatal spiny projection neurons (SPNs). We examined whether dopaminergic neuromodulation regulates activity-dependent glutamatergic synapse formation in the developing striatum. Systemic in vivo treatment with Gαs-coupled G-protein receptors (GPCRs) agonists enhanced excitatory synapses on direct pathway striatal spiny projection neurons (dSPNs), whereas rapid production of excitatory synapses on indirect pathway neurons (iSPNs) required the activation of Gαs GPCRs in SPNs of both pathways. Nevertheless, in vitro Gαs activation was sufficient to enhance spinogenesis induced by glutamate photolysis in both dSPNs and iSPNs, suggesting that iSPNs in intact neural circuits have additional requirements for rapid synaptic development. We evaluated the in vivo effects of enhanced glutamate release from corticostriatal axons and postsynaptic PKA and discovered a mechanism of developmental plasticity, wherein rapid synaptogenesis is promoted by the coordinated actions of glutamate and postsynaptic Gαs-coupled receptors.
    Full-text · Article · Nov 2015 · eLife Sciences
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    • "Indeed, cell death can be induced by non-innervation at the peak of synaptogenesis during embryonic and postnatal development (Naruse and Keino, 1995). Since activation of NMDARs has been shown to support new spine formation (Maletic-Savatic et al., 1999; Kwon and Sabatini, 2011), we hypothesize that NMDAR is required for initial spine gain on dendrites of newborn GCs and that insufficient spine growth may be the underlying cause of the cell death associated with the genetic deletion of the NMDAR subunit NR1 in newborn GCs. There is a positive correlation between spine volume and the number of AMPA (α-amino-3- hydroxy-5-methyl-4-isoxazole propionic acid) receptors (AMPARs) or, more generally, the synaptic strength (Matsuzaki et al., 2001), supporting the model that spine outgrowth and enlargement are tightly coupled to the formation and maturation of glutamatergic synapses (Zito et al., 2009). "
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    ABSTRACT: NMDA receptor (NMDAR)-dependent forms of synaptic plasticity are thought to underlie the assembly of developing neuronal circuits and to play a crucial role in learning and memory. It remains unclear how NMDAR might contribute to the wiring of adult-born granule cells (GCs). Here we demonstrate that nascent GCs lacking NMDARs but rescued from apoptosis by overexpressing the pro-survival protein Bcl2 were deficient in spine formation. Insufficient spinogenesis might be a general cause of cell death restricted within the NMDAR-dependent critical time window for GC survival. NMDAR loss also led to enhanced mushroom spine formation and synaptic AMPAR activity throughout the development of newborn GCs. Moreover, similar elevated synapse maturation in the absence of NMDARs was observed in neonate-generated GCs and CA1 pyramidal neurons. Together, these data suggest that NMDAR operates as a molecular monitor for controlling the activity-dependent establishment and maturation rate of synaptic connections between newborn neurons and others.
    Full-text · Article · Oct 2015 · eLife Sciences
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    • "The current model suggests that immature filopodia search for presynaptic termini in their environment and then transform into mature dendritic spines when they respond to neurotransmitter stimulation (Maletic-Savatic et al., 1999; Marrs et al., 2001; Trachtenberg et al., 2002; Zuo et al., 2005; De Roo et al., 2008). In addition to transforming from dendritic filopodia, dendritic spines also emerge directly from dendritic shaft upon local glutamate stimulation in brain slice culture (Kwon and Sabatini, 2011). Thus, multiple pathways are involved in dendritic Additional Supporting Information may be found in the online version of this article. "
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    ABSTRACT: Dendritic spines are the major locations of excitatory synapses in the mammalian central nervous system. The transformation from dendritic filopodia to dendritic spines has been recognized as one type of spinogenesis. For instance, syndecan-2 (SDC2), a synaptic heparan sulfate proteoglycan, is highly concentrated at dendritic spines and required for spinogenesis. It induces dendritic filopodia formation, followed by spine formation. However, the molecular regulation of the filopodium-spine transition induced by SDC2 is still unclear. In this report, we show that calcium is an important signal downstream of SDC2 in regulation of filopodium-spine transition but not filopodia formation. SDC2 interacted with the postsynaptic proteins CASK and LIN7 and further recruited NMDAR to the tips of filopodia induced by SDC2. Calcium influx via NMDAR promoted spine maturation because addition of EDTA or AP5 to the culture medium effectively prevented morphological change from dendritic filopodia to dendritic spines. Our data also indicated that F-actin rearrangement regulated by calcium influx is involved in the morphological change, because the knockdown of gelsolin, a calcium-activated F-actin severing molecule, impaired the filopodium-spine transition induced by SDC2. In conclusion, our study demonstrates that postsynaptic proteins coordinate to trigger calcium signalling and cytoskeleton rearrangement and consequently control filopodium-spine transition. © 2014 Wiley Periodicals, Inc. Develop Neurobiol, 2014
    Preview · Article · Oct 2014 · Developmental Neurobiology
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