Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome
Gal Hacohen-Kleiman, … , R. Anne McKinney, Illana Gozes
Gal Hacohen-Kleiman, … , R. Anne McKinney, Illana Gozes
Published November 1, 2018; First published August 14, 2018
Citation Information: J Clin Invest. 2018;128(11):4956-4969. https://doi.org/10.1172/JCI98199.
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Research Article Therapeutics

Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome

Abstract

Previous findings showed that in mice, complete knockout of activity-dependent neuroprotective protein (ADNP) abolishes brain formation, while haploinsufficiency (Adnp+/–) causes cognitive impairments. We hypothesized that mutations in ADNP lead to a developmental/autistic syndrome in children. Indeed, recent phenotypic characterization of children harboring ADNP mutations (ADNP syndrome children) revealed global developmental delays and intellectual disabilities, including speech and motor dysfunctions. Mechanistically, ADNP includes a SIP motif embedded in the ADNP-derived snippet drug candidate NAP (NAPVSIPQ, also known as CP201), which binds to microtubule end–binding protein 3, essential for dendritic spine formation. Here, we established a unique neuronal membrane–tagged, GFP-expressing Adnp+/– mouse line allowing in vivo synaptic pathology quantification. We discovered that Adnp deficiency reduced dendritic spine density and altered synaptic gene expression, both of which were partly ameliorated by NAP treatment. Adnp+/–mice further exhibited global developmental delays, vocalization impediments, gait and motor dysfunctions, and social and object memory impairments, all of which were partially reversed by daily NAP administration (systemic/nasal). In conclusion, we have connected ADNP-related synaptic pathology to developmental and behavioral outcomes, establishing NAP in vivo target engagement and identifying potential biomarkers. Together, these studies pave a path toward the clinical development of NAP (CP201) for the treatment of ADNP syndrome.

Authors

Gal Hacohen-Kleiman, Shlomo Sragovich, Gidon Karmon, Andy Y. L. Gao, Iris Grigg, Metsada Pasmanik-Chor, Albert Le, Vlasta Korenková, R. Anne McKinney, Illana Gozes

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Figure 1

Adnp+/– mice, compared with Adnp+/+ mice, display a significant decrease in hippocampal dendritic spine density that is ameliorated by NAP.

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Adnp+/– mice, compared with Adnp+/+ mice, display a significant decreas...
Average total spine density (males: Adnp+/+ n = 84, Adnp+/– n = 75, Adnp+/– NAP, n = 73; females: Adnp+/+ n = 48, Adnp+/– n = 45, Adnp+/– NAP, n = 45 dendrites/experimental group) and shaft synapse density (males: Adnp+/+ n = 11, Adnp+/– n = 15, Adnp+/– NAP, n = 10; females: Adnp+/+ n = 11, Adnp+/– n = 19, Adnp+/– NAP, n = 19 dendrites/experimental group). Total spine density was significantly decreased in both male and female Adnp+/– mice, with NAP significantly increasing spine density. Shaft synapse density was significantly increased in males and reduced by NAP in both sexes. A 2-way ANOVA with Tukey’s post hoc test was performed. Underlined numbers beneath the graphs represent the mean ± SEM. (A) In male mice, for total spine density, main genotype [F(1,290) = 62.278, P < 0.001] and interaction [F(1,290) = 31.385, P < 0.001] effects were found. For shaft synapses, main genotype [F(1,42) = 23.358, P < 0.001] and treatment [F(1,42) = 9.752, P = 0.003] effects were found. Tukey’s post hoc test revealed significant differences between Adnp+/+ and Adnp+/– mice (***P < 0.001) and between NAP- and vehicle-treated Adnp+/– mice (**P < 0.01 and ***P < 0.001). (B) In female mice, for total spine density, main genotype [F(1,183) = 9.327, P = 0.003], treatment [F(1,183) = 11.167, P = 0.001], and interaction [F(1,183) = 17.332, P < 0.001] effects were found. For shaft synapses, a main treatment effect was found [F(1,71) = 13.726, P < 0.001]. Tukey’s post hoc test revealed significant differences between Adnp+/+ and Adnp+/– mice (***P < 0.001) and between NAP- and vehicle-treated Adnp+/– mice (**P < 0.01 and ***P < 0.001). (A and B) Adnp+/+ data are reshown in Supplemental Figure 1, A and B. Scale bars: 2 μm.