[article]
| Titre : |
Altered Striatal Synaptic Function and Abnormal Behaviour in Shank3 Exon4-9 Deletion Mouse Model of Autism |
| Type de document : |
texte imprimé |
| Auteurs : |
Thomas C. JARAMILLO, Auteur ; Haley E. SPEED, Auteur ; Zhong XUAN, Auteur ; Jeremy M. REIMERS, Auteur ; Shunan LIU, Auteur ; Craig M. POWELL, Auteur |
| Article en page(s) : |
p.350-375 |
| Langues : |
Anglais (eng) |
| Mots-clés : |
autism spectrum disorder Shank3 Phelan-McDermid syndrome mouse model grooming |
| Index. décimale : |
PER Périodiques |
| Résumé : |
Shank3 is a multi-domain, synaptic scaffolding protein that organizes proteins in the postsynaptic density of excitatory synapses. Clinical studies suggest that ∼0.5% of autism spectrum disorder (ASD) cases may involve SHANK3 mutation/deletion. Patients with SHANK3 mutations exhibit deficits in cognition along with delayed/impaired speech/language and repetitive and obsessive/compulsive-like (OCD-like) behaviors. To examine how mutation/deletion of SHANK3 might alter brain function leading to ASD, we have independently created mice with deletion of Shank3 exons 4-9, a region implicated in ASD patients. We find that homozygous deletion of exons 4-9 (Shank3e4-9 KO) results in loss of the two highest molecular weight isoforms of Shank3 and a significant reduction in other isoforms. Behaviorally, both Shank3e4-9 heterozygous (HET) and Shank3e4-9 KO mice display increased repetitive grooming, deficits in novel and spatial object recognition learning and memory, and abnormal ultrasonic vocalizations. Shank3e4-9 KO mice also display abnormal social interaction when paired with one another. Analysis of synaptosome fractions from striata of Shank3e4-9 KO mice reveals decreased Homer1b/c, GluA2, and GluA3 expression. Both Shank3e4-9 HET and KO demonstrated a significant reduction in NMDA/AMPA ratio at excitatory synapses onto striatal medium spiny neurons. Furthermore, Shank3e4-9 KO mice displayed reduced hippocampal LTP despite normal baseline synaptic transmission. Collectively these behavioral, biochemical and physiological changes suggest Shank3 isoforms have region-specific roles in regulation of AMPAR subunit localization and NMDAR function in the Shank3e4-9 mutant mouse model of autism. Autism Res 2016, 9: 350–375. © 2015 International Society for Autism Research, Wiley Periodicals, Inc. |
| En ligne : |
http://dx.doi.org/10.1002/aur.1529 |
| Permalink : |
https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=285 |
in Autism Research > 9-3 (March 2016) . - p.350-375
[article] Altered Striatal Synaptic Function and Abnormal Behaviour in Shank3 Exon4-9 Deletion Mouse Model of Autism [texte imprimé] / Thomas C. JARAMILLO, Auteur ; Haley E. SPEED, Auteur ; Zhong XUAN, Auteur ; Jeremy M. REIMERS, Auteur ; Shunan LIU, Auteur ; Craig M. POWELL, Auteur . - p.350-375. Langues : Anglais ( eng) in Autism Research > 9-3 (March 2016) . - p.350-375
| Mots-clés : |
autism spectrum disorder Shank3 Phelan-McDermid syndrome mouse model grooming |
| Index. décimale : |
PER Périodiques |
| Résumé : |
Shank3 is a multi-domain, synaptic scaffolding protein that organizes proteins in the postsynaptic density of excitatory synapses. Clinical studies suggest that ∼0.5% of autism spectrum disorder (ASD) cases may involve SHANK3 mutation/deletion. Patients with SHANK3 mutations exhibit deficits in cognition along with delayed/impaired speech/language and repetitive and obsessive/compulsive-like (OCD-like) behaviors. To examine how mutation/deletion of SHANK3 might alter brain function leading to ASD, we have independently created mice with deletion of Shank3 exons 4-9, a region implicated in ASD patients. We find that homozygous deletion of exons 4-9 (Shank3e4-9 KO) results in loss of the two highest molecular weight isoforms of Shank3 and a significant reduction in other isoforms. Behaviorally, both Shank3e4-9 heterozygous (HET) and Shank3e4-9 KO mice display increased repetitive grooming, deficits in novel and spatial object recognition learning and memory, and abnormal ultrasonic vocalizations. Shank3e4-9 KO mice also display abnormal social interaction when paired with one another. Analysis of synaptosome fractions from striata of Shank3e4-9 KO mice reveals decreased Homer1b/c, GluA2, and GluA3 expression. Both Shank3e4-9 HET and KO demonstrated a significant reduction in NMDA/AMPA ratio at excitatory synapses onto striatal medium spiny neurons. Furthermore, Shank3e4-9 KO mice displayed reduced hippocampal LTP despite normal baseline synaptic transmission. Collectively these behavioral, biochemical and physiological changes suggest Shank3 isoforms have region-specific roles in regulation of AMPAR subunit localization and NMDAR function in the Shank3e4-9 mutant mouse model of autism. Autism Res 2016, 9: 350–375. © 2015 International Society for Autism Research, Wiley Periodicals, Inc. |
| En ligne : |
http://dx.doi.org/10.1002/aur.1529 |
| Permalink : |
https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=285 |
|  |
Altered Striatal Synaptic Function and Abnormal Behaviour in Shank3 Exon4-9 Deletion Mouse Model of Autism in Autism Research, 9-3 (March 2016)
