Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2.
Autism spectrum disorders comprise a range of neurodevelopmental disorders characterized by deficits in social interaction and communication, and by repetitive behaviour. Mutations in synaptic proteins such as neuroligins, neurexins, GKAPs/SAPAPs and ProSAPs/Shanks were identified in patients with autism spectrum disorder, but the causative mechanisms remain largely unknown. ProSAPs/Shanks build large homo- and heteromeric protein complexes at excitatory synapses and organize the complex protein machinery of the postsynaptic density in a laminar fashion. Here we demonstrate that genetic deletion of ProSAP1/Shank2 results in an early, brain-region-specific upregulation of ionotropic glutamate receptors at the synapse and increased levels of ProSAP2/Shank3. Moreover, ProSAP1/Shank2(-/-) mutants exhibit fewer dendritic spines and show reduced basal synaptic transmission, a reduced frequency of miniature excitatory postsynaptic currents and enhanced N-methyl-d-aspartate receptor-mediated excitatory currents at the physiological level. Mutants are extremely hyperactive and display profound autistic-like behavioural alterations including repetitive grooming as well as abnormalities in vocal and social behaviours. By comparing the data on ProSAP1/Shank2(-/-) mutants with ProSAP2/Shank3αβ(-/-) mice, we show that different abnormalities in synaptic glutamate receptor expression can cause alterations in social interactions and communication. Accordingly, we propose that appropriate therapies for autism spectrum disorders are to be carefully matched to the underlying synaptopathic phenotype.
Institute for Anatomy and Cell Biology, Ulm University, 89081 Ulm, Germany.
Michael J
MJ
Schmeisser
Elodie
E
Ey
Stephanie
S
Wegener
Juergen
J
Bockmann
A Vanessa
AV
Stempel
Angelika
A
Kuebler
Anna-Lena
AL
Janssen
Patrick T
PT
Udvardi
Ehab
E
Shiban
Christina
C
Spilker
Detlef
D
Balschun
Boris V
BV
Skryabin
Susanne tom
St
Dieck
Karl-Heinz
KH
Smalla
Dirk
D
Montag
Claire S
CS
Leblond
Philippe
P
Faure
Nicolas
N
Torquet
Anne-Marie
AM
Le Sourd
Roberto
R
Toro
Andreas M
AM
Grabrucker
Sarah A
SA
Shoichet
Dietmar
D
Schmitz
Michael R
MR
Kreutz
Thomas
T
Bourgeron
Eckart D
ED
Gundelfinger
Tobias M
TM
Boeckers
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D001321:Autistic Disorder / Q000235:genetics* / Q000473:pathology; D001522:Behavior, Animal / Q000502:physiology*; D049229:Dendritic Spines / Q000235:genetics; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics*; D011595:Psychomotor Agitation / Q000235:genetics* / Q000473:pathology; D058468:Receptors, Ionotropic Glutamate / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D015854:Up-Regulation; D014828:Vocalization, Animal / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D009419:Nerve Tissue Proteins; D058468:Receptors, Ionotropic Glutamate; C488222:Shank2 protein, mouse