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Effects of in utero Exposure to CASP...

Su, Julia Y,

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Effects of in utero Exposure to CASPR2 Autoantibodies on Neurodevelopment and Autism Spectrum Disorder /

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Effects of in utero Exposure to CASPR2 Autoantibodies on Neurodevelopment and Autism Spectrum Disorder // Julia Y Su.
作者:	Su, Julia Y,
面頁冊數:	1 electronic resource (110 pages)
附註:	Source: Dissertations Abstracts International, Volume: 84-07, Section: B.
Contained By:	Dissertations Abstracts International84-07B.
標題:	Neurosciences. -
電子資源:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30246374
ISBN:	9798368437439

Effects of in utero Exposure to CASPR2 Autoantibodies on Neurodevelopment and Autism Spectrum Disorder /
Su, Julia Y,

Effects of in utero Exposure to CASPR2 Autoantibodies on Neurodevelopment and Autism Spectrum Disorder /Julia Y Su. - 1 electronic resource (110 pages)

Source: Dissertations Abstracts International, Volume: 84-07, Section: B.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and restricted interests and motor behaviors. There has been an increasing amount of evidence suggesting ASD as a neurodevelopmental disease that starts in the womb. Women with autoimmune diseases are more likely to harbor anti-brain antibodies and more likely to have a child with ASD. Of women who have a child with ASD and anti-brain antibodies, 37% of them have antibodies against contactin-associated protein like 2 (CASPR2). When an anti-CASPR2 antibody (C6) was cloned from a human mother to a child with ASD was injected into pregnant mice, the male offspring had ASD-like behavioral phenotypes and neuroanatomical changes. Similarly, when female mice that were immunized with the human extracellular portion of CASPR2 were set into pregnancies, their male offspring once again had ASD-like behavioral phenotypes and neuroanatomical changes. In this thesis, we explored the heterogeneity of anti-CASPR2 autoantibodies and their contribution to ASD development in utero. To do this, we generated 4 unique monoclonal antibodies against CASPR2 (P11G7, P9C7, P13F4, and P6B2) and tested their binding profiles against a variety of assays. Each antibody had a unique binding profile. P11G7 and P9C7 are IgG1 antibodies that bind to the discoidin domain. P13F4 bound to multiple domains in CASPR2 and P6B2's binding site is still unknown and both are IgG2b antibodies. Male mice that were exposed to P9C7 or P6B2 in utero were less social in the direct social interaction test. Male mice exposed to P13F4 in utero were hyperactive as seen in the open field task. To explore the molecular mechanism of anti-CASPR2 antibodies, we looked at GluA1 and CASPR2 internalization on neuronal cultures. Only P13F4-exposed neurons showed a significant internalization of both CASPR2 and GluA1. Our findings show that not all anti-CASPR2 antibodies are pathogenic nor are they pathogenic in the same way. We also showed that one potential molecular mechanism underlying these antibodies involved CASPR2 and GluA1 internalization.

English

ISBN: 9798368437439Subjects--Topical Terms:

588700
Neurosciences.
Subjects--Index Terms:

Autism spectrum disorder

Effects of in utero Exposure to CASPR2 Autoantibodies on Neurodevelopment and Autism Spectrum Disorder /
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520 $a Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and restricted interests and motor behaviors. There has been an increasing amount of evidence suggesting ASD as a neurodevelopmental disease that starts in the womb. Women with autoimmune diseases are more likely to harbor anti-brain antibodies and more likely to have a child with ASD. Of women who have a child with ASD and anti-brain antibodies, 37% of them have antibodies against contactin-associated protein like 2 (CASPR2). When an anti-CASPR2 antibody (C6) was cloned from a human mother to a child with ASD was injected into pregnant mice, the male offspring had ASD-like behavioral phenotypes and neuroanatomical changes. Similarly, when female mice that were immunized with the human extracellular portion of CASPR2 were set into pregnancies, their male offspring once again had ASD-like behavioral phenotypes and neuroanatomical changes. In this thesis, we explored the heterogeneity of anti-CASPR2 autoantibodies and their contribution to ASD development in utero. To do this, we generated 4 unique monoclonal antibodies against CASPR2 (P11G7, P9C7, P13F4, and P6B2) and tested their binding profiles against a variety of assays. Each antibody had a unique binding profile. P11G7 and P9C7 are IgG1 antibodies that bind to the discoidin domain. P13F4 bound to multiple domains in CASPR2 and P6B2's binding site is still unknown and both are IgG2b antibodies. Male mice that were exposed to P9C7 or P6B2 in utero were less social in the direct social interaction test. Male mice exposed to P13F4 in utero were hyperactive as seen in the open field task. To explore the molecular mechanism of anti-CASPR2 antibodies, we looked at GluA1 and CASPR2 internalization on neuronal cultures. Only P13F4-exposed neurons showed a significant internalization of both CASPR2 and GluA1. Our findings show that not all anti-CASPR2 antibodies are pathogenic nor are they pathogenic in the same way. We also showed that one potential molecular mechanism underlying these antibodies involved CASPR2 and GluA1 internalization.
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