Dynamics of the mouse brain cortical synaptic proteome during postnatal brain development

Gonzalez‐Lozano, Miguel A.; Klemmer, Patricia; Gebuis, Titia; Hassan, Chopie; Nierop, Pim van; Kesteren, Ronald E. van; Smit, August B.; Li, Ka Wan

doi:10.1038/srep35456

Cited by 72 publications

(169 citation statements)

References 65 publications

(90 reference statements)

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“…This suggests that synapses at this developing stage may have already assembled the majority of proteins as when they mature, although the synapses are still scarce on spines but increase steadily within the first few weeks of rodent life. This is in line with a recent report showing that the same number of synaptic membrane proteins were identified across the ages of P9 to P280 with differences in abundance of many of them over time [13]. Core presynaptic and postsynaptic proteins are revealed at low levels at P9 with an overall increase in expression levels or subunit shift during development [13].…”

Section: Discussionsupporting

confidence: 90%

“…To discover the novel proteins that have not been reported in previous synapse proteomic studies, proteins identified in this work were compared to published data from six other proteomic experiments with the PSD or synaptic membrane fractions [1,4,5,7,13,27]. Of the 512 proteins identified with high confidence, 452 were detected in mature or immature synapses by MS, while 60 have not been reported in previous PSD or synapse proteomes (underlined in Supplemental Table S1).…”

Section: Resultsmentioning

confidence: 99%

“…Recent synaptic proteomic studies in postnatal brain have provided valuable resource for understanding the enhanced plasticity during critical periods and possible synaptic deficits underlying developmental brain disorders [13–15]. The present work focused on profiling postsynaptic density proteins from P9 mouse cortex.…”

Section: Discussionmentioning

confidence: 99%

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Proteomic Analysis of Mouse Cortex Postsynaptic Density following Neonatal Brain Hypoxia-Ischemia

Shao

Wang²,

Guan³

et al. 2017

Dev Neurosci

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Proteomics of the synapses and postsynaptic densities (PSDs) have provided a deep understanding of protein composition and signal networks in the adult brain, which underlie neuronal plasticity and neurodegenerative or psychiatric disorders. However, there is a paucity of knowledge about the architecture and organization of PSDs in the immature brain, and how it is modified by brain injury in an early developing stage. Mass spectrometry (MS)-based proteomic analysis was performed on PSDs prepared from cortices of postnatal day 9 naïve mice or pups which had suffered hypoxic-ischemic (HI) brain injury. 512 proteins of different functional groups were identified from PSDs collected 1 h after HI injury, among which 60 have not been reported previously. Seven newly identified proteins involved in neural development were highlighted. HI injury increased the yield of PSDs at early time points upon reperfusion, and multiple proteins were recruited into PSDs following the insult. Quantitative analysis was performed using spectral counting, and proteins whose relative expression was more than 50% up- or downregulated compared to the sham animals 1 h after HI insult were reported. Validation with Western blotting demonstrated changes in expression and phosphorylation of the N-methyl-D-aspartate receptor, activation of a series of postsynaptic protein kinases and dysregulation of scaffold and adaptor proteins in response to neonatal HI insult. This work, along with other recent studies of synaptic protein profiling in the immature brain, builds a foundation for future investigation on the molecular mechanisms underlying developing plasticity. Furthermore, it provides insights into the biochemical changes of PSDs following early brain hypoxia-ischemia, which is helpful for understanding not only the injury mechanisms, but also the process of repair or replenishment of neuronal circuits during recovery from brain damage.

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Section: Discussionsupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

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Proteomic Analysis of Mouse Cortex Postsynaptic Density following Neonatal Brain Hypoxia-Ischemia

Shao

Wang²,

Guan³

et al. 2017

Dev Neurosci

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“…However, gel-based proteomics applications have important limitations, the most significant of which are the inability to detect low-abundance proteins and the difficulty of resolving membrane-bound proteins [74]. Several previous studies have examined the synaptic fraction of the mPFC proteome in developing rodents [17–20], thus the present findings add to a preexisting literature by shedding light on the whole-cell protein alterations occurring during adolescent brain maturation. Still, the methods used in these experiments leave open the strong possibility that additional proteins not detected here may be altered during cortical development.…”

Section: Discussionmentioning

confidence: 82%

Comparison of the adolescent and adult mouse prefrontal cortex proteome

et al. 2017

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Adolescence is a developmental period characterized by unique behavioral phenotypes (increased novelty seeking, risk taking, sociability and impulsivity) and increased risk for destructive behaviors, impaired decision making and psychiatric illness. Adaptive and maladaptive adolescent traits have been associated with development of the medial prefrontal cortex (mPFC), a brain region that mediates regulatory control of behavior. However, the molecular changes that underlie brain development and behavioral vulnerability have not been fully characterized. Using high-throughput 2D DIGE spot profiling with identification by MALDI-TOF mass spectrometry, we identified 62 spots in the PFC that exhibited age-dependent differences in expression. Identified proteins were associated with diverse cellular functions, including intracellular signaling, synaptic plasticity, cellular organization and metabolism. Separate Western blot analyses confirmed age-related changes in DPYSL2, DNM1, STXBP1 and CFL1 in the mPFC and expanded these findings to the dorsal striatum, nucleus accumbens, motor cortex, amygdala and ventral tegmental area. Ingenuity Pathway Analysis (IPA) identified functional interaction networks enriched with proteins identified in the proteomics screen, linking age-related alterations in protein expression to cellular assembly and development, cell signaling and behavior, and psychiatric illness. These results provide insight into potential molecular components of adolescent cortical development, implicating structural processes that begin during embryonic development as well as plastic adaptations in signaling that may work in concert to bring the cortex, and other brain regions, into maturity.

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“…In the mouse cortical synaptoproteome DCAKD has been found to be among the proteins with the highest changes between juvenile postnatal days and adult stage, which suggests a putative role in brain development 41,42 .…”

Section: Dcakdmentioning

confidence: 99%

Genomic dissection of bipolar disorder and schizophrenia including 28 subphenotypes

Knight

2017

Preprint

141

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Schizophrenia (SCZ) and bipolar disorder (BD) are highly heritable disorders that share a significant proportion of common risk variation. Understanding the genetic factors underlying the specific symptoms of these disorders will be crucial for improving diagnosis, intervention and treatment. In case-control data consisting of 53,555 cases (20,129 BD,33,426 SCZ) and 54,065 controls, we identified 114 genome-wide significant loci (GWS) when comparing all cases to controls, of which 41 represented novel findings. Two genome-wide significant loci were identified when comparing SCZ to BD and a third was found when directly incorporating functional information. Regional joint association identified a genomic region of overlapping association in BD and SCZ with disease-independent causal variants indicating a fourth region contributing to differences between these disorders. Regional SNP-heritability analyses demonstrated that the estimated heritability of BD based on the SCZ GWS regions was significantly higher than that based on the average genomic region (91 regions, p = 1. have identified specific loci pointing to a potential role of 4 genes (DARS2, ARFGEF2, DCAKD and GATAD2A) that distinguish between BD and SCZ, providing an opportunity to understand . CC-BY-NC-ND 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/173435 doi: bioRxiv preprint first posted online Aug. 8, 2017; the biology contributing to clinical differences of these disorders. Our results provide the best evidence so far of genomic components distinguishing between BD and SCZ that contribute directly to specific symptom dimensions.

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Dynamics of the mouse brain cortical synaptic proteome during postnatal brain development

Cited by 72 publications

References 65 publications

Proteomic Analysis of Mouse Cortex Postsynaptic Density following Neonatal Brain Hypoxia-Ischemia

Proteomic Analysis of Mouse Cortex Postsynaptic Density following Neonatal Brain Hypoxia-Ischemia

Comparison of the adolescent and adult mouse prefrontal cortex proteome

Genomic dissection of bipolar disorder and schizophrenia including 28 subphenotypes

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