Association of mouse Dlg4 (PSD-95) gene deletion and human DLG4 gene variation with phenotypes relevant to autism spectrum disorders and Williams' syndrome.
OBJECTIVE
Research is increasingly linking autism spectrum disorders and other neurodevelopmental disorders to synaptic abnormalities ("synaptopathies"). PSD-95 (postsynaptic density-95, DLG4) orchestrates protein-protein interactions at excitatory synapses and is a major functional bridge interconnecting a neurexinneuroligin-SHANK pathway implicated in autism spectrum disorders.


METHODS
The authors characterized behavioral, dendritic, and molecular phenotypic abnormalities relevant to autism spectrum disorders in mice with PSD-95 deletion (Dlg4⁻(/)⁻). The data from mice led to the identification of single-nucleotide polymorphisms (SNPs) in human DLG4 and the examination of associations between these variants and neural signatures of Williams' syndrome in a normal population, using functional and structural neuroimaging.


RESULTS
Dlg4⁻(/)⁻ showed increased repetitive behaviors, abnormal communication and social behaviors, impaired motor coordination, and increased stress reactivity and anxiety-related responses. Dlg4⁻(/)⁻ had subtle dysmorphology of amygdala dendritic spines and altered forebrain expression of various synaptic genes, including Cyln2, which regulates cytoskeletal dynamics and is a candidate gene for Williams' syndrome. A signifi-cant association was observed between variations in two human DLG4 SNPs and reduced intraparietal sulcus volume and abnormal cortico-amygdala coupling, both of which characterize Williams' syndrome.


CONCLUSIONS
These findings demonstrate that DLG4 gene disruption in mice produces a complex range of behavioral and molecular abnormalities relevant to autism spectrum disorders and Williams' syndrome. The study provides an initial link between human DLG4 gene variation and key neural endophenotypes of Williams' syndrome and perhaps corticoamygdala regulation of emotional and social processes more generally.
Feyder
Michael
M
Section on Behavioral Science and Genetics, Laboratory for Integrative Neuroscience, National Institute on Alcoholism and Alcohol Abuse, Rockville, MD 20852-9411, USA. michael.feyder@ki.se
Karlsson
Rose-Marie
RM
Mathur
Poonam
P
Lyman
Matthew
M
Bock
Roland
R
Momenan
Reza
R
Munasinghe
Jeeva
J
Scattoni
Maria Luisa
ML
Ihne
Jessica
J
Camp
Marguerite
M
Graybeal
Carolyn
C
Strathdee
Douglas
D
Begg
Alison
A
Alvarez
Veronica A
VA
Kirsch
Peter
P
Rietschel
Marcella
M
Cichon
Sven
S
Walter
Henrik
H
Meyer-Lindenberg
Andreas
A
Grant
Seth G N
SG
Holmes
Andrew
A
D000328:Adult; D000679:Amygdala / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D000818:Animals; D001522:Behavior, Animal; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics* / Q000473:pathology; D049229:Dendritic Spines / Q000648:ultrastructure; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D005260:Female; D017353:Gene Deletion; D014644:Genetic Variation; D051528:Guanylate Kinases; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009434:Neural Pathways / Q000473:pathology; D010296:Parietal Lobe / Q000473:pathology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D016548:Prosencephalon / Q000378:metabolism; D018980:Williams Syndrome / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology
C501444:DLG4 protein, human; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D051528:Guanylate Kinases