Human genetic studies are rapidly identifying variants that increase risk for neurodevelopmental disorders. However, it remains unclear how specific mutations impact brain function and contribute to neuropsychiatric risk. Chromosome 16p11.2 deletion is one of the most common copy number variations in autism and related neurodevelopmental disorders. Using resting state functional MRI data from the Simons Variation in Individuals Project (VIP) database, we show that 16p11.2 deletion carriers exhibit impaired prefrontal connectivity, resulting in weaker long-range functional coupling with temporal-parietal regions. These functional changes are associated with socio-cognitive impairments. We also document that a mouse with the same genetic deficiency exhibits similarly diminished prefrontal connectivity, together with thalamo-prefrontal miswiring and reduced long-range functional synchronization. These results reveal a mechanistic link between specific genetic risk for neurodevelopmental disorders and long-range functional coupling, and suggest that deletion in 16p11.2 may lead to impaired socio-cognitive function via dysregulation of prefrontal connectivity.

Autism-associated 16p11.2 microdeletion impairs prefrontal functional connectivity in mouse and human

Parolisi, Roberta;Buffo, Annalisa;
2018

Abstract

Human genetic studies are rapidly identifying variants that increase risk for neurodevelopmental disorders. However, it remains unclear how specific mutations impact brain function and contribute to neuropsychiatric risk. Chromosome 16p11.2 deletion is one of the most common copy number variations in autism and related neurodevelopmental disorders. Using resting state functional MRI data from the Simons Variation in Individuals Project (VIP) database, we show that 16p11.2 deletion carriers exhibit impaired prefrontal connectivity, resulting in weaker long-range functional coupling with temporal-parietal regions. These functional changes are associated with socio-cognitive impairments. We also document that a mouse with the same genetic deficiency exhibits similarly diminished prefrontal connectivity, together with thalamo-prefrontal miswiring and reduced long-range functional synchronization. These results reveal a mechanistic link between specific genetic risk for neurodevelopmental disorders and long-range functional coupling, and suggest that deletion in 16p11.2 may lead to impaired socio-cognitive function via dysregulation of prefrontal connectivity.
141
7
2055-2065
2065
fMRI; DMN; resting; state; thalamus; imaging
Bertero, Alice; Liska, Adam; Pagani, Marco; Parolisi, Roberta; Masferrer, Maria Esteban; Gritti, Marta; Pedrazzoli, Matteo; Galbusera, Alberto; Sarica, Alessia; Cerasa, Antonio; Buffelli, Ario; Tonini, Raffaella; Buffo, Annalisa; Gross, Cornelius; Pasqualetti, Massimo; Gozzi, Alessandro
File in questo prodotto:
File Dimensione Formato  
Bertero 2018.pdf

Accesso aperto

Descrizione: Bertero et al 2018
Tipo di file: PDF EDITORIALE
Dimensione 879.97 kB
Formato Adobe PDF
879.97 kB Adobe PDF Visualizza/Apri
Brain_2018.pdf

Accesso riservato

Tipo di file: PDF EDITORIALE
Dimensione 909.46 kB
Formato Adobe PDF
909.46 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1671438
Citazioni
  • ???jsp.display-item.citation.pmc??? 42
  • Scopus 57
  • ???jsp.display-item.citation.isi??? 56
social impact