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Persistent microglial activation and synaptic loss with behavioral abnormalities in mouse offspring exposed to CASPR2-antibodies in utero

Persistent microglial activation and synaptic loss with behavioral abnormalities in mouse offspring exposed to CASPR2-antibodies in utero
Persistent microglial activation and synaptic loss with behavioral abnormalities in mouse offspring exposed to CASPR2-antibodies in utero

Gestational transfer of maternal antibodies against fetal neuronal proteins may be relevant to some neurodevelopmental disorders, but until recently there were no proteins identified. We recently reported a fivefold increase in CASPR2-antibodies in mid-gestation sera from mothers of children with intellectual and motor disabilities. Here, we exposed mice in utero to purified IgG from patients with CASPR2-antibodies (CASPR2-IgGs) or from healthy controls (HC-IgGs). CASPR2-IgG but not HC-IgG bound to fetal brain parenchyma, from which CASPR2-antibodies could be eluted. CASPR2-IgG exposed neonates achieved milestones similarly to HC-IgG exposed controls but, when adult, the CASPR2-IgG exposed progeny showed marked social interaction deficits, abnormally located glutamatergic neurons in layers V–VI of the somatosensory cortex, a 16% increase in activated microglia, and a 15–52% decrease in glutamatergic synapses in layers of the prefrontal and somatosensory cortices. Thus, in utero exposure to CASPR2-antibodies led to permanent behavioral, cellular, and synaptic abnormalities. These findings support a pathogenic role for maternal antibodies in human neurodevelopmental conditions, and CASPR2 as a potential target.

Autism, CASPR2, Intellectual development, Maternal antibodies, Maternal-to-fetal mouse model, Neurodevelopmental disorders
0001-6322
567-583
Coutinho, Ester
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Menassa, David A.
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Jacobson, Leslie
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West, Steven J.
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Domingos, Joana
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Moloney, Teresa C.
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Lang, Bethan
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Harrison, Paul J.
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Bennett, David L.H.
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Bannerman, David
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Vincent, Angela
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Coutinho, Ester
60bc1126-35c9-4631-86cc-b20e44396fb4
Menassa, David A.
eeb394a6-c72b-49d7-a820-95b0256c22d5
Jacobson, Leslie
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West, Steven J.
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Domingos, Joana
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Moloney, Teresa C.
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Lang, Bethan
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Harrison, Paul J.
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Bennett, David L.H.
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Bannerman, David
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Vincent, Angela
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Coutinho, Ester, Menassa, David A., Jacobson, Leslie, West, Steven J., Domingos, Joana, Moloney, Teresa C., Lang, Bethan, Harrison, Paul J., Bennett, David L.H., Bannerman, David and Vincent, Angela (2017) Persistent microglial activation and synaptic loss with behavioral abnormalities in mouse offspring exposed to CASPR2-antibodies in utero. Acta Neuropathologica, 134 (4), 567-583. (doi:10.1007/s00401-017-1751-5).

Record type: Article

Abstract

Gestational transfer of maternal antibodies against fetal neuronal proteins may be relevant to some neurodevelopmental disorders, but until recently there were no proteins identified. We recently reported a fivefold increase in CASPR2-antibodies in mid-gestation sera from mothers of children with intellectual and motor disabilities. Here, we exposed mice in utero to purified IgG from patients with CASPR2-antibodies (CASPR2-IgGs) or from healthy controls (HC-IgGs). CASPR2-IgG but not HC-IgG bound to fetal brain parenchyma, from which CASPR2-antibodies could be eluted. CASPR2-IgG exposed neonates achieved milestones similarly to HC-IgG exposed controls but, when adult, the CASPR2-IgG exposed progeny showed marked social interaction deficits, abnormally located glutamatergic neurons in layers V–VI of the somatosensory cortex, a 16% increase in activated microglia, and a 15–52% decrease in glutamatergic synapses in layers of the prefrontal and somatosensory cortices. Thus, in utero exposure to CASPR2-antibodies led to permanent behavioral, cellular, and synaptic abnormalities. These findings support a pathogenic role for maternal antibodies in human neurodevelopmental conditions, and CASPR2 as a potential target.

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10.1007_s00401-017-1751-5 - Version of Record
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Accepted/In Press date: 13 July 2017
e-pub ahead of print date: 28 July 2017
Published date: 1 October 2017
Keywords: Autism, CASPR2, Intellectual development, Maternal antibodies, Maternal-to-fetal mouse model, Neurodevelopmental disorders

Identifiers

Local EPrints ID: 417406
URI: http://eprints.soton.ac.uk/id/eprint/417406
ISSN: 0001-6322
PURE UUID: 52cd9bc5-4e11-43a6-add9-7507f3378b9a

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Date deposited: 30 Jan 2018 17:32
Last modified: 15 Mar 2024 16:32

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Contributors

Author: Ester Coutinho
Author: David A. Menassa
Author: Leslie Jacobson
Author: Steven J. West
Author: Joana Domingos
Author: Teresa C. Moloney
Author: Bethan Lang
Author: Paul J. Harrison
Author: David L.H. Bennett
Author: David Bannerman
Author: Angela Vincent

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