Netrin-1 Promotes Excitatory Synaptogenesis between Cortical Neurons by Initiating Synapse Assembly

Goldman, Jennifer S.; Ashour, Mohammed A.; Magdesian, Margaret H.; Tritsch, Nicolas X.; Harris, Stephanie N.; Christofi, Nicolas; Chemali, Raja; Stern, Yaakov E.; Thompson-Steckel, Greta; Gris, Pavel; Glasgow, Stephen D.; Grütter, Peter; Bouchard, Jean‐François; Ruthazer, Edward S.; Stellwagen, David; Kennedy, Timothy E.

doi:10.1523/jneurosci.1085-13.2013

Cited by 112 publications

(130 citation statements)

References 47 publications

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“…4A and 4B); consistent with earlier work using cortical neurons. [36][37][52][53] The presence of receptors in all subcellular regions is in agreement with the notion that neurons may be sensing differences in Netrin-1 concentration along their entire lengths to modulate their elongation rates, and across their growth cones to modulate turning responses. Signal intensities were measured at three axonal regions of interest (ROIs): axon shafts, growth cones and filopodia (Fig.…”

supporting

confidence: 82%

Neuron Subpopulations with Different Elongation Rates and DCC Dynamics Exhibit Distinct Responses to Isolated Netrin-1 Treatment

Blasiak

Kilinc

2015

ACS Chem. Neurosci.

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Correct wiring of the nervous system requires guidance cues, diffusible or substrate-bound proteins that steer elongating axons to their target tissues. Netrin-1, the best characterized member of the Netrins family of guidance molecules, is known to induce axon turning and modulate axon elongation rate; however, the factors regulating the axonal response to Netrin-1 are not fully understood. Using microfluidics, we treated fluidically-isolated axons of mouse primary cortical neurons with Netrin-1 and characterized axon elongation rates, as well as the membrane localization of deleted in colorectal cancer (DCC), a well-established receptor of Netrin-1. The capacity to stimulate and observe a large number of individual axons allowed us to conduct distribution analyses, through which we identified two distinct neuron sub-populations based on different elongation behavior and different DCC membrane dynamics. Netrin-1 reduced the elongation rates in both sub-populations, where the effect was more pronounced in the slow growing sub-population. Both the source of Ca 2+ influx and the basal cytosolic Ca 2+ levels regulated the effect of Netrin-1, e.g., Ca 2+ efflux from the endoplasmic reticulum due to the activation of Ryanodine channels blocked Netrin-1-induced axon slowdown. Netrin-1 treatment resulted in a rapid membrane insertion of DCC, followed by a gradual internalization. DCC membrane dynamics were different in the central regions of the growth cones compared to filopodia and axon shafts, highlighting the temporal and spatial heterogeneity in the signaling events downstream of Netrin-1. Cumulatively, these results demonstrate the power of microfluidic compartmentalization and distribution analysis in describing the complex axonal Netrin-1 response.

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supporting

confidence: 82%

Neuron Subpopulations with Different Elongation Rates and DCC Dynamics Exhibit Distinct Responses to Isolated Netrin-1 Treatment

Blasiak

Kilinc

2015

ACS Chem. Neurosci.

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“…Therefore, amphetamine in adolescence may 'denude' dopamine axons by limiting the DCC/netrin-1 interaction. Indeed DCC-mediated netrin-1 signaling promotes synaptogenesis in vitro by increasing the probability of axon-dendrite adhesion and, in turn, triggering the formation of presynaptic sites (Goldman et al, 2013). Here, we show that netrin-1 mRNA expression in the mPFC during adolescent synaptic organization is not altered by exposure to amphetamine.…”

Section: Dcc-mediated Effects Of Amphetamine On the Sculpting Of Mpfcmentioning

confidence: 54%

Amphetamine in Adolescence Disrupts the Development of Medial Prefrontal Cortex Dopamine Connectivity in a dcc-Dependent Manner

Reynolds

Makowski

Yogendran

et al. 2014

Neuropsychopharmacol

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Initiation of drug use during adolescence is a strong predictor of both the incidence and severity of addiction throughout the lifetime. Intriguingly, adolescence is a period of dynamic refinement in the organization of neuronal connectivity, in particular medial prefrontal cortex (mPFC) dopamine circuitry. The guidance cue receptor, DCC (deleted in colorectal cancer), is highly expressed by dopamine neurons and orchestrates their innervation to the mPFC during adolescence. Furthermore, we have shown that amphetamine in adolescence regulates DCC expression in dopamine neurons. Drugs in adolescence may therefore induce their enduring behavioral effects via DCC-mediated disruption in mPFC dopamine development. In this study, we investigated the impact of repeated exposure to amphetamine during adolescence on both the development of mPFC dopamine connectivity and on salience attribution to drug context in adulthood. We compare these effects to those induced by adult exposure to an identical amphetamine regimen. Finally, we determine whether DCC signaling within dopamine neurons is necessary for these events. Exposure to amphetamine in adolescence, but not in adulthood, leads to an increase in the span of dopamine innervation to the mPFC, but a reduction of presynaptic sites present on these axons. Amphetamine treatment in adolescence, but not in adulthood, also produces an increase in salience attribution to a previously drug-paired context in adulthood. Remarkably, DCC signaling within dopamine neurons is required for both of these effects. Drugs of abuse in adolescence may therefore induce their detrimental behavioral consequences by disrupting mesocortical dopamine development through alterations in the DCC signaling cascade.

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“…Moreover, we apply these methods at two developmental time points: postnatal day 17 (P17), within a period of peak synaptogenesis (21), and adulthood (P45). Stable isotope labeling in mammals (SILAM) enables complete labeling of amino acids with 15 N in the whole animal, including rodents (22,23).…”

mentioning

confidence: 99%

Fmr1 deficiency promotes age-dependent alterations in the cortical synaptic proteome

Tang

Wang

Wan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Fragile X syndrome (FXS) is an X-linked neurodevelopmental disorder characterized by severe intellectual disability and other symptoms including autism. Although caused by the silencing of a single gene, Fmr1 (fragile X mental retardation 1), the complexity of FXS pathogenesis is amplified because the encoded protein, FMRP, regulates the activity-dependent translation of numerous mRNAs. Although the mRNAs that associate with FMRP have been extensively studied, little is known regarding the proteins whose expression levels are altered, directly or indirectly, by loss of FMRP during brain development. Here we systematically measured protein expression in neocortical synaptic fractions from Fmr1 knockout (KO) and wild-type (WT) mice at both adolescent and adult stages. Although hundreds of proteins are up-regulated in the absence of FMRP in young mice, this up-regulation is largely diminished in adulthood. Up-regulated proteins included previously unidentified as well as known targets involved in synapse formation and function and brain development and others linked to intellectual disability and autism. Comparison with putative FMRP target mRNAs and autism susceptibility genes revealed substantial overlap, consistent with the idea that the autism endophenotype of FXS is due to a "multiple hit" effect of FMRP loss, particularly within the PSD95 interactome. Through studies of de novo protein synthesis in primary cortical neurons from KO and WT mice, we found that neurons lacking FMRP produce nascent proteins at higher rates, many of which are synaptic proteins and encoded by FMRP target mRNAs. Our results provide a greatly expanded view of protein changes in FXS and identify age-dependent effects of FMRP in shaping the neuronal proteome.fragile X | quantitative mass spectrometry | synaptic protein synthesis | autism | stable isotope labeling F ragile X syndrome (FXS) is an X-linked monogenic disorder that leads to highly debilitating changes in neurodevelopment. Affected individuals exhibit mental retardation, attention deficit and hyperactivity, anxiety, autism spectrum behaviors, and other symptoms that compound overall impairment (1). In the vast majority of cases, FXS is caused by an mRNA-dependent epigenetic silencing of the Fmr1 (fragile X mental retardation 1) gene (2), which occurs secondarily to a CGG repeat expansion in the 5′ UTR region of Fmr1 (3) and results in absence of the encoded protein FMRP. FMRP is an RNA-binding protein that regulates several aspects of mRNA translation (1), transport (4), and stability (5) in neurons. Substantial evidence indicates that FMRP is particularly critical as a suppressor of activity-dependent mRNA translation at glutamatergic synapses (6, 7) and that loss of this function results in abnormalities in dendritic spine shape and several forms of long-term synaptic plasticity (8, 9). In addition, significant changes have been described regarding the structure and/or function of other synaptic systems, including GABAergic and endocannabinoid synapses (10, 11). Loss of FMR...

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Netrin-1 Promotes Excitatory Synaptogenesis between Cortical Neurons by Initiating Synapse Assembly

Cited by 112 publications

References 47 publications

Neuron Subpopulations with Different Elongation Rates and DCC Dynamics Exhibit Distinct Responses to Isolated Netrin-1 Treatment

Neuron Subpopulations with Different Elongation Rates and DCC Dynamics Exhibit Distinct Responses to Isolated Netrin-1 Treatment

Amphetamine in Adolescence Disrupts the Development of Medial Prefrontal Cortex Dopamine Connectivity in a dcc-Dependent Manner

Fmr1 deficiency promotes age-dependent alterations in the cortical synaptic proteome

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