p(HGNC:ADNP)

Entity

Name

ADNP

Namespace

hgnc

Namespace Version

20190224

Namespace URL

https://raw.githubusercontent.com/pharmacome/terminology/efc856fb009a39e4d284269a6801f79ed3d3cf56/external/hgnc-names.belns

A reduction of ADNP and its homologous protein, ADNP2, is observed in schizophrenic patients [254], and it is recapitulated in Map6-deficient (Map6+/-) mice, another transgenic model of schizophrenia PubMed:30061532

Additionally, given that ADNP and NAP are linked with autophagy (13), cell adhesion (35), immune response (36), autism (6, 13, 15, 17, 27), and synapse-related processes (6), the analysis included several representative genes pertaining to these processes PubMed:30106381

We evaluated the 31 transcripts regulated at both tested ages (see above) and found that the most enriched modified functions were related to nervous system development and activity including synapse assembly, positive regulation of synaptic transmission, glutamatergic, regulation of synapse organization, regulation of cell communication, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) glutamate receptor clustering, learning or memory, social behavior, regulation of ion transport, vocalization behavior, and nervous system development (Figure 3, Supplemental Tables 11 and 12) PubMed:30106381

Additionally, given that ADNP and NAP are linked with autophagy (13), cell adhesion (35), immune response (36), autism (6, 13, 15, 17, 27), and synapse-related processes (6), the analysis included several representative genes pertaining to these processes PubMed:30106381

Additionally, given that ADNP and NAP are linked with autophagy (13), cell adhesion (35), immune response (36), autism (6, 13, 15, 17, 27), and synapse-related processes (6), the analysis included several representative genes pertaining to these processes PubMed:30106381

We evaluated the 31 transcripts regulated at both tested ages (see above) and found that the most enriched modified functions were related to nervous system development and activity including synapse assembly, positive regulation of synaptic transmission, glutamatergic, regulation of synapse organization, regulation of cell communication, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) glutamate receptor clustering, learning or memory, social behavior, regulation of ion transport, vocalization behavior, and nervous system development (Figure 3, Supplemental Tables 11 and 12) PubMed:30106381

We evaluated the 31 transcripts regulated at both tested ages (see above) and found that the most enriched modified functions were related to nervous system development and activity including synapse assembly, positive regulation of synaptic transmission, glutamatergic, regulation of synapse organization, regulation of cell communication, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) glutamate receptor clustering, learning or memory, social behavior, regulation of ion transport, vocalization behavior, and nervous system development (Figure 3, Supplemental Tables 11 and 12) PubMed:30106381

We evaluated the 31 transcripts regulated at both tested ages (see above) and found that the most enriched modified functions were related to nervous system development and activity including synapse assembly, positive regulation of synaptic transmission, glutamatergic, regulation of synapse organization, regulation of cell communication, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) glutamate receptor clustering, learning or memory, social behavior, regulation of ion transport, vocalization behavior, and nervous system development (Figure 3, Supplemental Tables 11 and 12) PubMed:30106381

We evaluated the 31 transcripts regulated at both tested ages (see above) and found that the most enriched modified functions were related to nervous system development and activity including synapse assembly, positive regulation of synaptic transmission, glutamatergic, regulation of synapse organization, regulation of cell communication, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) glutamate receptor clustering, learning or memory, social behavior, regulation of ion transport, vocalization behavior, and nervous system development (Figure 3, Supplemental Tables 11 and 12) PubMed:30106381

We evaluated the 31 transcripts regulated at both tested ages (see above) and found that the most enriched modified functions were related to nervous system development and activity including synapse assembly, positive regulation of synaptic transmission, glutamatergic, regulation of synapse organization, regulation of cell communication, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) glutamate receptor clustering, learning or memory, social behavior, regulation of ion transport, vocalization behavior, and nervous system development (Figure 3, Supplemental Tables 11 and 12) PubMed:30106381

Additionally, given that ADNP and NAP are linked with autophagy (13), cell adhesion (35), immune response (36), autism (6, 13, 15, 17, 27), and synapse-related processes (6), the analysis included several representative genes pertaining to these processes PubMed:30106381

ADNP expression in lymphocytes correlates with inflammation levels (36), disease state, and autophagy (13), as well as intelligence (40). PubMed:30106381

We evaluated the 31 transcripts regulated at both tested ages (see above) and found that the most enriched modified functions were related to nervous system development and activity including synapse assembly, positive regulation of synaptic transmission, glutamatergic, regulation of synapse organization, regulation of cell communication, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) glutamate receptor clustering, learning or memory, social behavior, regulation of ion transport, vocalization behavior, and nervous system development (Figure 3, Supplemental Tables 11 and 12) PubMed:30106381

We evaluated the 31 transcripts regulated at both tested ages (see above) and found that the most enriched modified functions were related to nervous system development and activity including synapse assembly, positive regulation of synaptic transmission, glutamatergic, regulation of synapse organization, regulation of cell communication, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) glutamate receptor clustering, learning or memory, social behavior, regulation of ion transport, vocalization behavior, and nervous system development (Figure 3, Supplemental Tables 11 and 12) PubMed:30106381

Figure 3, Supplemental Figure 5 (younger age group), Supplemental Figure 6 (older age group), and Supplemental Tables 5 and 8 reveal an overall similar pattern of Adnp genotype–and NAP treatment–regulated human and mouse protein product interactions across ages with Akt1 (the mosaic mutations of which lead to the Proteus syndrome, characterized by the overgrowth of skin, connective tissue, brain, and other tissues; ref. 37) and discs large MAGUK scaffold protein 4 (Dlg4, also known as Psd95), a key regulator of synaptic plasticity (see above) that plays central roles associated with ADNP and NAP function. PubMed:30106381

ADNP expression in lymphocytes correlates with inflammation levels (36), disease state, and autophagy (13), as well as intelligence (40). PubMed:30106381

In the 3-month-old hippocampi (Figure 4B), we found significant sex-dependent changes for Adnp+/– gene regulation and NAP rescue in the following genes in male mice: (a) apolipoprotein E (Apoe), the lead gene for Alzheimer’s disease risk, which was shown before to be a major gene regulated by ADNP (10, 13); (b) Gm21949, which is suggested to play a role in calcium-mediated responses, action potential conduction in myelinated cells, and axonal outgrowth and guidance (6); (c) lipase A (Lipa), which is related to lipid metabolism and was previously shown to be regulated by the Adnp genotype in mice (3); (d) autism-associated neuroligin 2 (Nlgn2), a postsynaptic membrane cell adhesion protein that mediates the formation and maintenance of synapses between neurons (12); (e) paired box protein 6 (Pax6), a key regulator in glutamatergic neuronal differentiation (38) and cortical development (39), which was shown before by us to be regulated by ADNP (complete knockout of Adnp rendered Pax6 expression undetectable in the brain primordium, contrasting with increased expression in Adnp+/– embryos [ref. 1] and in subcortical brain domains of 2-month-old male Adnp+/– mice [ref. 3]); and (f) Wolframin endoplasmic reticulum transmembrane glycoprotein (Wfs1), which is associated with neurodegeneration and cellular calcium homeostasis regulation and was previously shown to be regulated by NAP (34). PubMed:30106381

In the 3-month-old hippocampi (Figure 4B), we found significant sex-dependent changes for Adnp+/– gene regulation and NAP rescue in the following genes in male mice: (a) apolipoprotein E (Apoe), the lead gene for Alzheimer’s disease risk, which was shown before to be a major gene regulated by ADNP (10, 13); (b) Gm21949, which is suggested to play a role in calcium-mediated responses, action potential conduction in myelinated cells, and axonal outgrowth and guidance (6); (c) lipase A (Lipa), which is related to lipid metabolism and was previously shown to be regulated by the Adnp genotype in mice (3); (d) autism-associated neuroligin 2 (Nlgn2), a postsynaptic membrane cell adhesion protein that mediates the formation and maintenance of synapses between neurons (12); (e) paired box protein 6 (Pax6), a key regulator in glutamatergic neuronal differentiation (38) and cortical development (39), which was shown before by us to be regulated by ADNP (complete knockout of Adnp rendered Pax6 expression undetectable in the brain primordium, contrasting with increased expression in Adnp+/– embryos [ref. 1] and in subcortical brain domains of 2-month-old male Adnp+/– mice [ref. 3]); and (f) Wolframin endoplasmic reticulum transmembrane glycoprotein (Wfs1), which is associated with neurodegeneration and cellular calcium homeostasis regulation and was previously shown to be regulated by NAP (34). PubMed:30106381

In the 3-month-old hippocampi (Figure 4B), we found significant sex-dependent changes for Adnp+/– gene regulation and NAP rescue in the following genes in male mice: (a) apolipoprotein E (Apoe), the lead gene for Alzheimer’s disease risk, which was shown before to be a major gene regulated by ADNP (10, 13); (b) Gm21949, which is suggested to play a role in calcium-mediated responses, action potential conduction in myelinated cells, and axonal outgrowth and guidance (6); (c) lipase A (Lipa), which is related to lipid metabolism and was previously shown to be regulated by the Adnp genotype in mice (3); (d) autism-associated neuroligin 2 (Nlgn2), a postsynaptic membrane cell adhesion protein that mediates the formation and maintenance of synapses between neurons (12); (e) paired box protein 6 (Pax6), a key regulator in glutamatergic neuronal differentiation (38) and cortical development (39), which was shown before by us to be regulated by ADNP (complete knockout of Adnp rendered Pax6 expression undetectable in the brain primordium, contrasting with increased expression in Adnp+/– embryos [ref. 1] and in subcortical brain domains of 2-month-old male Adnp+/– mice [ref. 3]); and (f) Wolframin endoplasmic reticulum transmembrane glycoprotein (Wfs1), which is associated with neurodegeneration and cellular calcium homeostasis regulation and was previously shown to be regulated by NAP (34). PubMed:30106381

Additionally, given that ADNP and NAP are linked with autophagy (13), cell adhesion (35), immune response (36), autism (6, 13, 15, 17, 27), and synapse-related processes (6), the analysis included several representative genes pertaining to these processes PubMed:30106381

ADNP expression in lymphocytes correlates with inflammation levels (36), disease state, and autophagy (13), as well as intelligence (40). PubMed:30106381

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 PubMed:30664622

In this respect, our previous data associated postsynaptic density protein 95 (PSD95, also known as DLG4) with ADNP/NAP activity PubMed:30664622

These results indicate that restoration of ADNP function by NAP administration rescues the wild type phenotype of the Adnp+/− mice, by reversing the abnormal increase in alcohol intake seen in Adnp haploinsufficient female mice PubMed:30008470

In addition, Adnp expression was increased at the 24 h time point in the NAc of female, but not male mouse (one-way ANOVA; females: F(2,9) = 10.87, p < 0.005; post hoc: p < 0.005; males: p > 0.05). PubMed:30008470

In addition, Adnp expression was increased at the 24 h time point in the NAc of female, but not male mouse (one-way ANOVA; females: F(2,9) = 10.87, p < 0.005; post hoc: p < 0.005; males: p > 0.05). PubMed:30008470

We found no changes in the expression of Adnp in the VTA (p’s > 0.05). PubMed:30008470

We found that among male mice, Adnp mRNA levels were increased in the dorsal hippocampus after a 24 h alcohol drinking session, but the level returned to baseline (water-drinking controls) after 24 h of withdrawal (Fig. 2b; one-way ANOVA: F(2,13) = 5.32, p < 0.05, post hoc comparisons, p’s < 0.05) PubMed:30008470

However, in female mice, the expression of Adnp was reduced after a 24-h alcohol-drinking session, and this reduction persisted after a 24-h withdrawal (Fig. 2c; one-way ANOVA: F(2,13) = 7.53, p < 0.01, post hoc comparisons, p’s < 0.05). PubMed:30008470

No changes in Adnp levels were detected in the VTA or NAc (p’s > 0.05). PubMed:30008470

ADNP is an essential protein for brain development and it has been shown to physically interact with a key protein in autophagosome biogenesis and maturation, namely LC3 PubMed:30061532

In this respect, our previous data associated postsynaptic density protein 95 (PSD95, also known as DLG4) with ADNP/NAP activity PubMed:30664622

Additionally, given that ADNP and NAP are linked with autophagy (13), cell adhesion (35), immune response (36), autism (6, 13, 15, 17, 27), and synapse-related processes (6), the analysis included several representative genes pertaining to these processes PubMed:30106381

ADNP expression in lymphocytes correlates with inflammation levels (36), disease state, and autophagy (13), as well as intelligence (40). PubMed:30106381

Additionally, given that ADNP and NAP are linked with autophagy (13), cell adhesion (35), immune response (36), autism (6, 13, 15, 17, 27), and synapse-related processes (6), the analysis included several representative genes pertaining to these processes PubMed:30106381

Additionally, given that ADNP and NAP are linked with autophagy (13), cell adhesion (35), immune response (36), autism (6, 13, 15, 17, 27), and synapse-related processes (6), the analysis included several representative genes pertaining to these processes PubMed:30106381

Additionally, given that ADNP and NAP are linked with autophagy (13), cell adhesion (35), immune response (36), autism (6, 13, 15, 17, 27), and synapse-related processes (6), the analysis included several representative genes pertaining to these processes PubMed:30106381

Additionally, given that ADNP and NAP are linked with autophagy (13), cell adhesion (35), immune response (36), autism (6, 13, 15, 17, 27), and synapse-related processes (6), the analysis included several representative genes pertaining to these processes PubMed:30106381

We evaluated the 31 transcripts regulated at both tested ages (see above) and found that the most enriched modified functions were related to nervous system development and activity including synapse assembly, positive regulation of synaptic transmission, glutamatergic, regulation of synapse organization, regulation of cell communication, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) glutamate receptor clustering, learning or memory, social behavior, regulation of ion transport, vocalization behavior, and nervous system development (Figure 3, Supplemental Tables 11 and 12) PubMed:30106381

We evaluated the 31 transcripts regulated at both tested ages (see above) and found that the most enriched modified functions were related to nervous system development and activity including synapse assembly, positive regulation of synaptic transmission, glutamatergic, regulation of synapse organization, regulation of cell communication, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) glutamate receptor clustering, learning or memory, social behavior, regulation of ion transport, vocalization behavior, and nervous system development (Figure 3, Supplemental Tables 11 and 12) PubMed:30106381

We evaluated the 31 transcripts regulated at both tested ages (see above) and found that the most enriched modified functions were related to nervous system development and activity including synapse assembly, positive regulation of synaptic transmission, glutamatergic, regulation of synapse organization, regulation of cell communication, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) glutamate receptor clustering, learning or memory, social behavior, regulation of ion transport, vocalization behavior, and nervous system development (Figure 3, Supplemental Tables 11 and 12) PubMed:30106381

We evaluated the 31 transcripts regulated at both tested ages (see above) and found that the most enriched modified functions were related to nervous system development and activity including synapse assembly, positive regulation of synaptic transmission, glutamatergic, regulation of synapse organization, regulation of cell communication, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) glutamate receptor clustering, learning or memory, social behavior, regulation of ion transport, vocalization behavior, and nervous system development (Figure 3, Supplemental Tables 11 and 12) PubMed:30106381

We evaluated the 31 transcripts regulated at both tested ages (see above) and found that the most enriched modified functions were related to nervous system development and activity including synapse assembly, positive regulation of synaptic transmission, glutamatergic, regulation of synapse organization, regulation of cell communication, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) glutamate receptor clustering, learning or memory, social behavior, regulation of ion transport, vocalization behavior, and nervous system development (Figure 3, Supplemental Tables 11 and 12) PubMed:30106381

We evaluated the 31 transcripts regulated at both tested ages (see above) and found that the most enriched modified functions were related to nervous system development and activity including synapse assembly, positive regulation of synaptic transmission, glutamatergic, regulation of synapse organization, regulation of cell communication, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) glutamate receptor clustering, learning or memory, social behavior, regulation of ion transport, vocalization behavior, and nervous system development (Figure 3, Supplemental Tables 11 and 12) PubMed:30106381

We evaluated the 31 transcripts regulated at both tested ages (see above) and found that the most enriched modified functions were related to nervous system development and activity including synapse assembly, positive regulation of synaptic transmission, glutamatergic, regulation of synapse organization, regulation of cell communication, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) glutamate receptor clustering, learning or memory, social behavior, regulation of ion transport, vocalization behavior, and nervous system development (Figure 3, Supplemental Tables 11 and 12) PubMed:30106381

We evaluated the 31 transcripts regulated at both tested ages (see above) and found that the most enriched modified functions were related to nervous system development and activity including synapse assembly, positive regulation of synaptic transmission, glutamatergic, regulation of synapse organization, regulation of cell communication, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) glutamate receptor clustering, learning or memory, social behavior, regulation of ion transport, vocalization behavior, and nervous system development (Figure 3, Supplemental Tables 11 and 12) PubMed:30106381

We evaluated the 31 transcripts regulated at both tested ages (see above) and found that the most enriched modified functions were related to nervous system development and activity including synapse assembly, positive regulation of synaptic transmission, glutamatergic, regulation of synapse organization, regulation of cell communication, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) glutamate receptor clustering, learning or memory, social behavior, regulation of ion transport, vocalization behavior, and nervous system development (Figure 3, Supplemental Tables 11 and 12) PubMed:30106381

We evaluated the 31 transcripts regulated at both tested ages (see above) and found that the most enriched modified functions were related to nervous system development and activity including synapse assembly, positive regulation of synaptic transmission, glutamatergic, regulation of synapse organization, regulation of cell communication, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) glutamate receptor clustering, learning or memory, social behavior, regulation of ion transport, vocalization behavior, and nervous system development (Figure 3, Supplemental Tables 11 and 12) PubMed:30106381

We evaluated the 31 transcripts regulated at both tested ages (see above) and found that the most enriched modified functions were related to nervous system development and activity including synapse assembly, positive regulation of synaptic transmission, glutamatergic, regulation of synapse organization, regulation of cell communication, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) glutamate receptor clustering, learning or memory, social behavior, regulation of ion transport, vocalization behavior, and nervous system development (Figure 3, Supplemental Tables 11 and 12) PubMed:30106381

In the 3-month-old hippocampi (Figure 4B), we found significant sex-dependent changes for Adnp+/– gene regulation and NAP rescue in the following genes in male mice: (a) apolipoprotein E (Apoe), the lead gene for Alzheimer’s disease risk, which was shown before to be a major gene regulated by ADNP (10, 13); (b) Gm21949, which is suggested to play a role in calcium-mediated responses, action potential conduction in myelinated cells, and axonal outgrowth and guidance (6); (c) lipase A (Lipa), which is related to lipid metabolism and was previously shown to be regulated by the Adnp genotype in mice (3); (d) autism-associated neuroligin 2 (Nlgn2), a postsynaptic membrane cell adhesion protein that mediates the formation and maintenance of synapses between neurons (12); (e) paired box protein 6 (Pax6), a key regulator in glutamatergic neuronal differentiation (38) and cortical development (39), which was shown before by us to be regulated by ADNP (complete knockout of Adnp rendered Pax6 expression undetectable in the brain primordium, contrasting with increased expression in Adnp+/– embryos [ref. 1] and in subcortical brain domains of 2-month-old male Adnp+/– mice [ref. 3]); and (f) Wolframin endoplasmic reticulum transmembrane glycoprotein (Wfs1), which is associated with neurodegeneration and cellular calcium homeostasis regulation and was previously shown to be regulated by NAP (34). PubMed:30106381

In the 3-month-old hippocampi (Figure 4B), we found significant sex-dependent changes for Adnp+/– gene regulation and NAP rescue in the following genes in male mice: (a) apolipoprotein E (Apoe), the lead gene for Alzheimer’s disease risk, which was shown before to be a major gene regulated by ADNP (10, 13); (b) Gm21949, which is suggested to play a role in calcium-mediated responses, action potential conduction in myelinated cells, and axonal outgrowth and guidance (6); (c) lipase A (Lipa), which is related to lipid metabolism and was previously shown to be regulated by the Adnp genotype in mice (3); (d) autism-associated neuroligin 2 (Nlgn2), a postsynaptic membrane cell adhesion protein that mediates the formation and maintenance of synapses between neurons (12); (e) paired box protein 6 (Pax6), a key regulator in glutamatergic neuronal differentiation (38) and cortical development (39), which was shown before by us to be regulated by ADNP (complete knockout of Adnp rendered Pax6 expression undetectable in the brain primordium, contrasting with increased expression in Adnp+/– embryos [ref. 1] and in subcortical brain domains of 2-month-old male Adnp+/– mice [ref. 3]); and (f) Wolframin endoplasmic reticulum transmembrane glycoprotein (Wfs1), which is associated with neurodegeneration and cellular calcium homeostasis regulation and was previously shown to be regulated by NAP (34). PubMed:30106381

Likewise, mechanistic target of rapamycin (Mtor), which has been linked to cellular regulation, protein translation, autophagy, and the actin cytoskeleton (43–45), was also found to be regulated by ADNP and NAP PubMed:30106381

In the 3-month-old hippocampi (Figure 4B), we found significant sex-dependent changes for Adnp+/– gene regulation and NAP rescue in the following genes in male mice: (a) apolipoprotein E (Apoe), the lead gene for Alzheimer’s disease risk, which was shown before to be a major gene regulated by ADNP (10, 13); (b) Gm21949, which is suggested to play a role in calcium-mediated responses, action potential conduction in myelinated cells, and axonal outgrowth and guidance (6); (c) lipase A (Lipa), which is related to lipid metabolism and was previously shown to be regulated by the Adnp genotype in mice (3); (d) autism-associated neuroligin 2 (Nlgn2), a postsynaptic membrane cell adhesion protein that mediates the formation and maintenance of synapses between neurons (12); (e) paired box protein 6 (Pax6), a key regulator in glutamatergic neuronal differentiation (38) and cortical development (39), which was shown before by us to be regulated by ADNP (complete knockout of Adnp rendered Pax6 expression undetectable in the brain primordium, contrasting with increased expression in Adnp+/– embryos [ref. 1] and in subcortical brain domains of 2-month-old male Adnp+/– mice [ref. 3]); and (f) Wolframin endoplasmic reticulum transmembrane glycoprotein (Wfs1), which is associated with neurodegeneration and cellular calcium homeostasis regulation and was previously shown to be regulated by NAP (34). PubMed:30106381

In the 3-month-old hippocampi (Figure 4B), we found significant sex-dependent changes for Adnp+/– gene regulation and NAP rescue in the following genes in male mice: (a) apolipoprotein E (Apoe), the lead gene for Alzheimer’s disease risk, which was shown before to be a major gene regulated by ADNP (10, 13); (b) Gm21949, which is suggested to play a role in calcium-mediated responses, action potential conduction in myelinated cells, and axonal outgrowth and guidance (6); (c) lipase A (Lipa), which is related to lipid metabolism and was previously shown to be regulated by the Adnp genotype in mice (3); (d) autism-associated neuroligin 2 (Nlgn2), a postsynaptic membrane cell adhesion protein that mediates the formation and maintenance of synapses between neurons (12); (e) paired box protein 6 (Pax6), a key regulator in glutamatergic neuronal differentiation (38) and cortical development (39), which was shown before by us to be regulated by ADNP (complete knockout of Adnp rendered Pax6 expression undetectable in the brain primordium, contrasting with increased expression in Adnp+/– embryos [ref. 1] and in subcortical brain domains of 2-month-old male Adnp+/– mice [ref. 3]); and (f) Wolframin endoplasmic reticulum transmembrane glycoprotein (Wfs1), which is associated with neurodegeneration and cellular calcium homeostasis regulation and was previously shown to be regulated by NAP (34). PubMed:30106381

In the 3-month-old hippocampi (Figure 4B), we found significant sex-dependent changes for Adnp+/– gene regulation and NAP rescue in the following genes in male mice: (a) apolipoprotein E (Apoe), the lead gene for Alzheimer’s disease risk, which was shown before to be a major gene regulated by ADNP (10, 13); (b) Gm21949, which is suggested to play a role in calcium-mediated responses, action potential conduction in myelinated cells, and axonal outgrowth and guidance (6); (c) lipase A (Lipa), which is related to lipid metabolism and was previously shown to be regulated by the Adnp genotype in mice (3); (d) autism-associated neuroligin 2 (Nlgn2), a postsynaptic membrane cell adhesion protein that mediates the formation and maintenance of synapses between neurons (12); (e) paired box protein 6 (Pax6), a key regulator in glutamatergic neuronal differentiation (38) and cortical development (39), which was shown before by us to be regulated by ADNP (complete knockout of Adnp rendered Pax6 expression undetectable in the brain primordium, contrasting with increased expression in Adnp+/– embryos [ref. 1] and in subcortical brain domains of 2-month-old male Adnp+/– mice [ref. 3]); and (f) Wolframin endoplasmic reticulum transmembrane glycoprotein (Wfs1), which is associated with neurodegeneration and cellular calcium homeostasis regulation and was previously shown to be regulated by NAP (34). PubMed:30106381

ADNP expression in lymphocytes correlates with inflammation levels (36), disease state, and autophagy (13), as well as intelligence (40). PubMed:30106381

ADNP expression in lymphocytes correlates with inflammation levels (36), disease state, and autophagy (13), as well as intelligence (40). PubMed:30106381

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). PubMed:30664622

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). PubMed:30664622

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) PubMed:30664622

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). PubMed:30664622

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 PubMed:30664622

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 PubMed:30664622

Fifty-two percent of the individuals in this cohort present with severe intellectual disability at the age of assessment, 36% have a moderate disability and 12% have a mild disability. PubMed:29724491

Developmental delay is present in all individuals, with motor delay being one of the key features. PubMed:29724491

Developmental delay is present in all individuals, with motor delay being one of the key features. PubMed:29724491

Seventy-eight percent of the children had hypotonia, while hypertonia was present in three children. PubMed:29724491

Seventy-eight percent of the children had hypotonia, while hypertonia was present in three children. PubMed:29724491

Another key feature is speech delay which presents in 98.6% of individuals. PubMed:29724491

Sixteen percent have seizures, including absence seizures, focal seizures with reduced awareness, epilepsy with Continuous Spike and Waves during Slow Wave Sleep (CSWS), or unclassified seizures. PubMed:29724491

Sixteen percent have seizures, including absence seizures, focal seizures with reduced awareness, epilepsy with Continuous Spike and Waves during Slow Wave Sleep (CSWS), or unclassified seizures. PubMed:29724491

Ninety-three percent of the individuals present with autistic features (Fig. 3-B). Sixty-seven percent of them have been reported to have a clinical diagnosis of ASD. PubMed:29724491

Ninety-three percent of the individuals present with autistic features (Fig. 3-B). Sixty-seven percent of them have been reported to have a clinical diagnosis of ASD. PubMed:29724491

Sixty-seven percent have also been diagnosed with sensory processing disorder. PubMed:29724491

Several present with obsessive compulsive behavior, mood disorder, a high anxiety level, temper tantrums, self-injurious and (verbally) aggressive behavior. PubMed:29724491

Several present with obsessive compulsive behavior, mood disorder, a high anxiety level, temper tantrums, self-injurious and (verbally) aggressive behavior. PubMed:29724491

Several present with obsessive compulsive behavior, mood disorder, a high anxiety level, temper tantrums, self-injurious and (verbally) aggressive behavior. PubMed:29724491

Several present with obsessive compulsive behavior, mood disorder, a high anxiety level, temper tantrums, self-injurious and (verbally) aggressive behavior. PubMed:29724491

Several present with obsessive compulsive behavior, mood disorder, a high anxiety level, temper tantrums, self-injurious and (verbally) aggressive behavior. PubMed:29724491

Several present with obsessive compulsive behavior, mood disorder, a high anxiety level, temper tantrums, self-injurious and (verbally) aggressive behavior. PubMed:29724491

Forty-four percent of the individuals are hyperactive or easily distracted. About one third of them have a diagnosis of Attention Deficit Hyperactivity Disorder (ADHD). PubMed:29724491

Sleep problems are present in 65.2%. PubMed:29724491

Fifty-six percent of them appeared to have cerebral abnormalities, including atypical white matter lesions, delayed myelination, cortical dysplasia or atrophy, perinatal hypoxic ischemic encephalopathy, hydrocephalus, and hippocampal hypoplasticity (Fig. 3-C) PubMed:29724491

Visual problems were present in 73.6% of the individuals, especially hypermetropia (40.3%) and strabismus (49.2%), but also myopia and astigmatism (Fig. 3-E). PubMed:29724491

Visual problems were present in 73.6% of the individuals, especially hypermetropia (40.3%) and strabismus (49.2%), but also myopia and astigmatism (Fig. 3-E). PubMed:29724491

Visual problems were present in 73.6% of the individuals, especially hypermetropia (40.3%) and strabismus (49.2%), but also myopia and astigmatism (Fig. 3-E). PubMed:29724491

Visual problems were present in 73.6% of the individuals, especially hypermetropia (40.3%) and strabismus (49.2%), but also myopia and astigmatism (Fig. 3-E). PubMed:29724491

Visual problems were present in 73.6% of the individuals, especially hypermetropia (40.3%) and strabismus (49.2%), but also myopia and astigmatism (Fig. 3-E). PubMed:29724491