1. Catalog
  2. Citations
  3. PubMed:30664622

PubMed: 30664622

Title
The autism/neuroprotection-linked ADNP/NAP regulate the excitatory glutamatergic synapse.
Journal
Translational psychiatry
Volume
9
Issue
None
Pages
2
Date
2019-01-15
Authors
Giladi E | Gozes I | Grigoriadis N | Lagoudaki R | Malishkevich A | Piontkewitz Y | Sragovich S | Touloumi O

Evidence 50890fc37c
JSON

We have previously shown essentially no significant NAP effects on behavior in the Adnp+/+ mice

a(PUBCHEM:9832404) causesNoChange bp(GO:behavior) View Subject | View Object

Appears in Networks:

Evidence dc0c6d1ede
JSON

Further results showed no significant brain penetration of Evans blue ( < 0.1 ng/ml, which was the limit of detection), and no difference between chlorobutanol and saline.

a(CHEBI:"Evans blue") causesNoChange tloc(a(PUBCHEM:9832404), fromLoc(GO:"extracellular region"), toLoc(MESH:Brain)) View Subject | View Object

Appears in Networks:

Evidence 8227ebab68
JSON

Representative pictures show penetration of the Evans blue dye in the periphery (Fig. 1d), but not in the brain (Fig. 1e), with brain concentration values < 0.03 ng/ml (Supplemental Fig. S1)

a(CHEBI:"Evans blue") increases tloc(a(PUBCHEM:9832404), fromLoc(GO:"extracellular region"), toLoc(GO:"cell periphery")) View Subject | View Object

Appears in Networks:

a(CHEBI:"Evans blue") causesNoChange tloc(a(PUBCHEM:9832404), fromLoc(GO:"extracellular region"), toLoc(MESH:Brain)) View Subject | View Object

Appears in Networks:

Evidence 2c91666cf8
JSON

Figure 1a shows enhanced brain/body bioavailability in the presence of the newly tested vehicle, chlorobutanol over time.

a(CHEBI:chlorobutanol) increases tloc(a(PUBCHEM:9832404), fromLoc(GO:"extracellular region"), toLoc(MESH:Brain)) View Subject | View Object

Appears in Networks:

a(CHEBI:chlorobutanol) increases tloc(a(PUBCHEM:9832404), fromLoc(GO:"extracellular region"), toLoc(MESH:"Cell Body")) View Subject | View Object

Appears in Networks:

Evidence 9125219d7f
JSON

Fig. 1b displays enhanced brain bioavailability by picture evaluation. Fig. 1c shows quantitative assessment of three independent experiments, revealing the dramatic 4-fold increase in specific brain bioavailability.

a(CHEBI:chlorobutanol) increases tloc(a(PUBCHEM:9832404), fromLoc(GO:"extracellular region"), toLoc(MESH:Brain)) View Subject | View Object

Appears in Networks:

Evidence 5f5546dffc
JSON

These findings provide clear evidence that the blood brain barrier remained intact in the presence of chlorobutanol

a(CHEBI:chlorobutanol) causesNoChange a(MESH:"Blood-Brain Barrier") View Subject | View Object

Appears in Networks:

Evidence 50a640046b
JSON

We have also extended the experiments to female mice, and interestingly, in the social recognition test CB- or NAP-treated females displayed significant preference to mice rather than objects (Supplemental Fig. S2C), unlike previous findings with the “DD” formulation.

a(CHEBI:chlorobutanol) increases bp(GO:"social behavior") View Subject | View Object

Appears in Networks:
Annotations
Gender
Female

a(PUBCHEM:9832404) increases bp(GO:"social behavior") View Subject | View Object

Appears in Networks:
Annotations
Gender
Female

composite(a(PUBCHEM:59557), a(PUBCHEM:9832404)) decreases bp(GO:"social behavior") View Subject | View Object

Appears in Networks:
Annotations
Gender
Female

Evidence 05420dcbf0
JSON

As social behavior depends on olfaction, this was also measured showing intact odor discrimination ability in CB-treated males (Fig. 2e) and a sex difference, with no preference for a specific olfactory cue in CB-treated females (Supplemental Fig. S2E), thus corroborating previous findings observed for DD-treated mice

a(CHEBI:chlorobutanol) causesNoChange path(MESH:Smell) View Subject | View Object

Appears in Networks:
Annotations
Gender
Male

a(CHEBI:chlorobutanol) decreases path(MESH:Smell) View Subject | View Object

Appears in Networks:
Annotations
Gender
Female

path(MESH:Smell) regulates bp(GO:"social behavior") View Subject | View Object

Appears in Networks:

Evidence ede9b98544
JSON

Our original cell culture results showed NAP protection against excitotoxicity over a broad concentration range, suggesting an involvement of the glutamatergic system in ADNP/NAP activity

a(GO:"glutamatergic synapse") association act(a(PUBCHEM:9832404)) View Subject | View Object

Appears in Networks:

a(GO:"glutamatergic synapse") association act(p(HGNC:ADNP)) View Subject | View Object

Appears in Networks:

a(PUBCHEM:9832404) decreases path(HBP:Excitotoxicity) View Subject | View Object

Appears in Networks:

act(a(PUBCHEM:9832404)) association a(GO:"glutamatergic synapse") View Subject | View Object

Appears in Networks:

act(p(HGNC:ADNP)) association a(GO:"glutamatergic synapse") View Subject | View Object

Appears in Networks:

Evidence 165f133eff
JSON

Furthermore, in both sexes, Adnp haploinsufficiency showed significantly inhibited social memory, which was completely ameliorated by NAP treatment (Fig. 2d, males and Supplemental Fig. S2D, females).

a(PUBCHEM:9832404) increases bp(GO:"social behavior") View Subject | View Object

Appears in Networks:
Annotations
Gender
Male
Gender
Female

p(HGNC:ADNP, pmod(MESH:Haploinsufficiency)) decreases bp(GO:"social behavior") View Subject | View Object

Appears in Networks:
Annotations
Gender
Male
Gender
Female

Evidence 810e2a74a4
JSON

Given the fact that children carrying ADNP mutations (ADNP syndrome children) exhibit motor impairments, we also utilized the hanging wire test to measure potential impairments and amelioration by NAP. Results showed a significant impairment due to Adnp haploinsufficiency and amelioration by NAP treatment (Fig. 2f)

a(PUBCHEM:9832404) decreases path(MESH:"Motor Skills Disorders") View Subject | View Object

Appears in Networks:

p(HGNC:ADNP, pmod(MESH:Haploinsufficiency)) increases path(MESH:"Motor Skills Disorders") View Subject | View Object

Appears in Networks:

p(HGNC:ADNP) decreases path(MESH:"Motor Skills Disorders") View Subject | View Object

Appears in Networks:

Evidence 8d00013892
JSON

In females, hippocampal VGLUT1 was not affected by the Adnp genotype or NAP treatment (Supplemental Fig. S4A)

a(PUBCHEM:9832404) causesNoChange p(HGNC:SLC17A7) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus
Gender
Female

p(HGNC:ADNP, pmod(MESH:Haploinsufficiency)) causesNoChange p(HGNC:SLC17A7) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus
Gender
Female

Evidence 97225454d7
JSON

In the cerebral cortex, female Adnp+/− mice exhibited significantly reduced VGLUT1 expression, with no effect for NAP (Supplemental Fig. S4B).

a(PUBCHEM:9832404) causesNoChange p(HGNC:SLC17A7) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
Gender
Female

p(HGNC:ADNP, pmod(MESH:Haploinsufficiency)) decreases p(HGNC:SLC17A7) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
Gender
Female

Evidence 940a1d457c
JSON

When using area counting, NAP treatment was shown to provide full protection against VGLUT1 decreases in both the hippocampus and the cerebral cortex (Fig. 4f, h), whereas in terms of intensity changes in VGLUT1 expression, NAP effect was significant in the hippocampus (Fig. 4g), and exhibited a trend of improvement in the cortex (Fig. 4i).

a(PUBCHEM:9832404) increases p(HGNC:SLC17A7) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

Evidence cd9e66757f
JSON

In males, complementing DTI data (Fig. 3) our results (Fig. 4a) revealed that in Adnp+/− mice, Slc17a7 (VGLUT1) gene expression was significantly decreased in the hippocampus, and completely reversed by NAP treatment (Fig. 4a), while in the cerebral cortex, NAP treatment resulted in a small, albeit significant decrease in the VGLUT1 transcript (Fig. 4b).

a(PUBCHEM:9832404) increases r(HGNC:SLC17A7) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus
Gender
Male

a(PUBCHEM:9832404) decreases r(HGNC:SLC17A7) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
Gender
Male

p(HGNC:ADNP, pmod(MESH:Haploinsufficiency)) decreases r(HGNC:SLC17A7) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus
Gender
Male

Evidence 3544a72121
JSON

In this respect, our previous data associated postsynaptic density protein 95 (PSD95, also known as DLG4) with ADNP/NAP activity

act(p(HGNC:ADNP)) association p(HGNC:DLG4) View Subject | View Object

Appears in Networks:

act(a(PUBCHEM:9832404)) association p(HGNC:DLG4) View Subject | View Object

Appears in Networks:

p(HGNC:DLG4) association act(a(PUBCHEM:9832404)) View Subject | View Object

Appears in Networks:

p(HGNC:DLG4) association act(p(HGNC:ADNP)) View Subject | View Object

Appears in Networks:

Evidence 6d361cf001
JSON

Adnp+/− mice compared with Adnp+/+ mice spent significantly shorter time periods in exploring the new objects, indicative of impaired memory, with intranasal NAP-CB treatment completely ameliorating this impairment (Fig. 2a, b).

composite(a(CHEBI:chlorobutanol), a(PUBCHEM:9832404)) increases bp(GO:memory) View Subject | View Object

Appears in Networks:

p(HGNC:ADNP, pmod(MESH:Haploinsufficiency)) decreases bp(GO:memory) View Subject | View Object

Appears in Networks:

p(HGNC:ADNP) increases bp(GO:memory) View Subject | View Object

Appears in Networks:

Evidence d9e6f2d39f
JSON

While no effect was observed in the Adnp+/− male mouse social recognition, with preference to mice rather than objects (Fig. 2c), Adnp haploinsufficiency showed significantly inhibited social memory, which was completely ameliorated by NAP-CB treatment (Fig. 2d).

composite(a(CHEBI:chlorobutanol), a(PUBCHEM:9832404)) increases bp(GO:"social behavior") View Subject | View Object

Appears in Networks:

p(HGNC:ADNP, pmod(MESH:Haploinsufficiency)) decreases bp(GO:"social behavior") View Subject | View Object

Appears in Networks:

p(HGNC:ADNP) increases bp(GO:"social behavior") View Subject | View Object

Appears in Networks:

Evidence 6bccaa5c4c
JSON

Furthermore, FA which is used to characterize the organization of white matter fibers, was shown to be significantly increased in Adnp+/− mice, thus implying of structural impairment. Importantly, this DTI observed structural impairment was ameliorated by NA-PCB treatment (Fig. 3b).

composite(a(CHEBI:chlorobutanol), a(PUBCHEM:9832404)) increases a(MESH:"Nerve Fibers, Myelinated") View Subject | View Object

Appears in Networks:
Annotations
MeSH
White Matter

p(HGNC:ADNP, pmod(MESH:Haploinsufficiency)) decreases a(MESH:"Nerve Fibers, Myelinated") View Subject | View Object

Appears in Networks:
Annotations
MeSH
White Matter

p(HGNC:ADNP) increases a(MESH:"Nerve Fibers, Myelinated") View Subject | View Object

Appears in Networks:
Annotations
MeSH
White Matter

Evidence 93e29cb0b0
JSON

Interestingly, in CB-treated males, Adnp haploinsufficiency showed a reduction in the total time spent with the different odors, which was significantly increased upon NAP treatment (Fig. 2e, inset).

composite(a(CHEBI:chlorobutanol), p(HGNC:ADNP, pmod(MESH:Haploinsufficiency))) decreases path(MESH:Smell) View Subject | View Object

Appears in Networks:
Annotations
Gender
Male

composite(a(PUBCHEM:9832404), p(HGNC:ADNP, pmod(MESH:Haploinsufficiency))) increases path(MESH:Smell) View Subject | View Object

Appears in Networks:
Annotations
Gender
Male

Evidence e4aae80ee9
JSON

As opposed to this, in females, CB-treated Adnp haploinsufficient mice showed significant increased total odor sniffing time, which was significantly reduced by NAP treatment (Supplemental Fig. S2E, inset).

composite(a(CHEBI:chlorobutanol), p(HGNC:ADNP, pmod(MESH:Haploinsufficiency))) increases path(MESH:Smell) View Subject | View Object

Appears in Networks:
Annotations
Gender
Female

composite(a(PUBCHEM:9832404), p(HGNC:ADNP, pmod(MESH:Haploinsufficiency))) decreases path(MESH:Smell) View Subject | View Object

Appears in Networks:
Annotations
Gender
Female

Evidence 31e74f54a7
JSON

Here, Adnp haploinsufficiency in male mice has led to a significant increased MD in the hippocampus (Fig. 3a).

p(HGNC:ADNP, pmod(MESH:Haploinsufficiency)) increases path(MESH:"Brain Injuries") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus
Gender
Male

Evidence 2340bd395e
JSON

At the protein level, a significant reduction in VGLUT1 was observed in both the hippocampus (Fig. 4c–e, immunohistochemistry, 4FG, densitometry) and cerebral cortex (Fig. 4h, i, densitometry).

p(HGNC:ADNP, pmod(MESH:Haploinsufficiency)) decreases p(HGNC:SLC17A7) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

Evidence ce9cab48dd
JSON

Also, as our previous experiments, labeling dendritic spines in vivo, showed reduction in spine density in the hippocampus and the cortex as a consequence of Adnp deficiency and protection by NAP injection, we now sought to determine possible genotype/treatment/sex effects on the vesicular glutamate transporter VGLUT1

p(HGNC:ADNP) increases a(GO:"dendritic spine") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

Evidence 90672855d8
JSON

VGLUT1 is both necessary and sufficient for uptake and storage of glutamate, and thus comprises the sole determinant for an excitatory glutamatergic phenotype

p(HGNC:SLC17A7) regulates bp(GO:"glutamate homeostasis") View Subject | View Object

Appears in Networks:

p(HGNC:SLC17A7) increases bp(GO:"L-glutamate import") View Subject | View Object

Appears in Networks:

About

BEL Commons is developed and maintained in an academic capacity by Charles Tapley Hoyt and Daniel Domingo-Fernández at the Fraunhofer SCAI Department of Bioinformatics with support from the IMI project, AETIONOMY. It is built on top of PyBEL, an open source project. Please feel free to contact us here to give us feedback or report any issues. Also, see our Publishing Notes and Data Protection information.

If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.