title: Dysfunctional cerebellar Purkinje cells contribute to autism-like behaviour in Shank2-deficient mice.
abstract: Loss-of-function mutations in the gene encoding the postsynaptic scaffolding protein SHANK2 are a highly penetrant cause of autism spectrum disorders (ASD) involving cerebellum-related motor problems. Recent studies have implicated cerebellar pathology in the aetiology of ASD. Here we evaluate the possibility that cerebellar Purkinje cells (PCs) represent a critical locus of ASD-like pathophysiology in mice lacking Shank2. Absence of Shank2 impairs both PC intrinsic plasticity and induction of long-term potentiation at the parallel fibre to PC synapse. Moreover, inhibitory input onto PCs is significantly enhanced, most prominently in the posterior lobe where simple spike (SS) regularity is most affected. Using PC-specific Shank2 knockouts, we replicate alterations of SS regularity in vivo and establish cerebellar dependence of ASD-like behavioural phenotypes in motor learning and social interaction. These data highlight the importance of Shank2 for PC function, and support a model by which cerebellar pathology is prominent in certain forms of ASD.
authors: Netherlands Institute for Neuroscience, Amsterdam 1105 CA, Netherlands.
authors: Saša
authors: S
authors: Peter
authors: Department of Neuroscience, Erasmus MC, Rotterdam 3000 DR, Netherlands.
authors: Michiel M
authors: MM
authors: Ten Brinke
authors: Department of Psychiatry, Erasmus MC, Rotterdam 3000 DR, Netherlands.
authors: Jeffrey
authors: J
authors: Stedehouder
authors: Institute for Anatomy and Cell Biology, Ulm University, Ulm 89081, Germany.
authors: Claudia M
authors: CM
authors: Reinelt
authors: Department of Neuroscience, Erasmus MC, Rotterdam 3000 DR, Netherlands.
authors: Bin
authors: B
authors: Wu
authors: Department of Neuroscience, Erasmus MC, Rotterdam 3000 DR, Netherlands.
authors: Haibo
authors: H
authors: Zhou
authors: Department of Neuroscience, Erasmus MC, Rotterdam 3000 DR, Netherlands.
authors: Kuikui
authors: K
authors: Zhou
authors: Department of Neuroscience, Erasmus MC, Rotterdam 3000 DR, Netherlands.
authors: Henk-Jan
authors: HJ
authors: Boele
authors: Department of Psychiatry, Erasmus MC, Rotterdam 3000 DR, Netherlands.
authors: Steven A
authors: 0000-0002-9777-3338
authors: SA
authors: Kushner
authors: Yonsei University College of Medicine, Seoul 120-752, Korea.
authors: Min Goo
authors: MG
authors: Lee
authors: Institute for Anatomy and Cell Biology, Ulm University, Ulm 89081, Germany.|Department of Neurology, Ulm University, Ulm 89081, Germany.
authors: Michael J
authors: MJ
authors: Schmeisser
authors: Institute for Anatomy and Cell Biology, Ulm University, Ulm 89081, Germany.
authors: Tobias M
authors: TM
authors: Boeckers
authors: Department of Neuroscience, Erasmus MC, Rotterdam 3000 DR, Netherlands.
authors: Martijn
authors: M
authors: Schonewille
authors: Department of Neuroscience, Erasmus MC, Rotterdam 3000 DR, Netherlands.
authors: Freek E
authors: FE
authors: Hoebeek
authors: Netherlands Institute for Neuroscience, Amsterdam 1105 CA, Netherlands.|Department of Neuroscience, Erasmus MC, Rotterdam 3000 DR, Netherlands.
authors: Chris I
authors: CI
authors: De Zeeuw
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000235:genetics* / Q000473:pathology*; D001522:Behavior, Animal / Q000502:physiology; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009473:Neuronal Plasticity / Q000235:genetics*; D011689:Purkinje Cells / Q000473:pathology*
chemical_list: D009419:Nerve Tissue Proteins; C488222:Shank2 protein, mouse