UBE3A expression during early postnatal brain development is required for proper dorsomedial striatal maturation
Angelman syndrome (AS) is a severe neurodevelopmental disorder (NDD) caused by loss of functional ubiquitin protein ligase E3A (UBE3A). Previous studies showed that UBE3A plays an important role in the first postnatal weeks of mouse brain development, but its precise role is unknown. Since impaired...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2023-02-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.166073 |
| _version_ | 1827768072579055616 |
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| author | Diana C. Rotaru Ilse Wallaard Maud de Vries Julia van der Bie Ype Elgersma |
| author_facet | Diana C. Rotaru Ilse Wallaard Maud de Vries Julia van der Bie Ype Elgersma |
| author_sort | Diana C. Rotaru |
| collection | DOAJ |
| description | Angelman syndrome (AS) is a severe neurodevelopmental disorder (NDD) caused by loss of functional ubiquitin protein ligase E3A (UBE3A). Previous studies showed that UBE3A plays an important role in the first postnatal weeks of mouse brain development, but its precise role is unknown. Since impaired striatal maturation has been implicated in several mouse models for NDDs, we studied the importance of UBE3A in striatal maturation. We used inducible Ube3a mouse models to investigate the maturation of medium spiny neurons (MSNs) from dorsomedial striatum. MSNs of mutant mice matured properly till postnatal day 15 (P15) but remained hyperexcitable with fewer excitatory synaptic events at later ages, indicative of stalled striatal maturation in Ube3a mice. Reinstatement of UBE3A expression at P21 fully restored MSN excitability but only partially restored synaptic transmission and the operant conditioning behavioral phenotype. Gene reinstatement at P70 failed to rescue both electrophysiological and behavioral phenotypes. In contrast, deletion of Ube3a after normal brain development did not result in these electrophysiological and behavioral phenotypes. This study emphasizes the role of UBE3A in striatal maturation and the importance of early postnatal reinstatement of UBE3A expression to obtain a full rescue of behavioral phenotypes associated with striatal function in AS. |
| first_indexed | 2024-03-11T12:07:04Z |
| format | Article |
| id | doaj.art-d9841b7b7061463b8375501fe47d00f0 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:07:04Z |
| publishDate | 2023-02-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-d9841b7b7061463b8375501fe47d00f02023-11-07T16:25:15ZengAmerican Society for Clinical investigationJCI Insight2379-37082023-02-0184UBE3A expression during early postnatal brain development is required for proper dorsomedial striatal maturationDiana C. RotaruIlse WallaardMaud de VriesJulia van der BieYpe ElgersmaAngelman syndrome (AS) is a severe neurodevelopmental disorder (NDD) caused by loss of functional ubiquitin protein ligase E3A (UBE3A). Previous studies showed that UBE3A plays an important role in the first postnatal weeks of mouse brain development, but its precise role is unknown. Since impaired striatal maturation has been implicated in several mouse models for NDDs, we studied the importance of UBE3A in striatal maturation. We used inducible Ube3a mouse models to investigate the maturation of medium spiny neurons (MSNs) from dorsomedial striatum. MSNs of mutant mice matured properly till postnatal day 15 (P15) but remained hyperexcitable with fewer excitatory synaptic events at later ages, indicative of stalled striatal maturation in Ube3a mice. Reinstatement of UBE3A expression at P21 fully restored MSN excitability but only partially restored synaptic transmission and the operant conditioning behavioral phenotype. Gene reinstatement at P70 failed to rescue both electrophysiological and behavioral phenotypes. In contrast, deletion of Ube3a after normal brain development did not result in these electrophysiological and behavioral phenotypes. This study emphasizes the role of UBE3A in striatal maturation and the importance of early postnatal reinstatement of UBE3A expression to obtain a full rescue of behavioral phenotypes associated with striatal function in AS.https://doi.org/10.1172/jci.insight.166073Cell biology |
| spellingShingle | Diana C. Rotaru Ilse Wallaard Maud de Vries Julia van der Bie Ype Elgersma UBE3A expression during early postnatal brain development is required for proper dorsomedial striatal maturation JCI Insight Cell biology |
| title | UBE3A expression during early postnatal brain development is required for proper dorsomedial striatal maturation |
| title_full | UBE3A expression during early postnatal brain development is required for proper dorsomedial striatal maturation |
| title_fullStr | UBE3A expression during early postnatal brain development is required for proper dorsomedial striatal maturation |
| title_full_unstemmed | UBE3A expression during early postnatal brain development is required for proper dorsomedial striatal maturation |
| title_short | UBE3A expression during early postnatal brain development is required for proper dorsomedial striatal maturation |
| title_sort | ube3a expression during early postnatal brain development is required for proper dorsomedial striatal maturation |
| topic | Cell biology |
| url | https://doi.org/10.1172/jci.insight.166073 |
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