Dysfunctional cerebellar Purkinje cells contribute to autism-like behaviour in Shank2-deficient mice

Saša Peter (), Michiel M. ten Brinke, Jeffrey Stedehouder, Claudia M. Reinelt, Bin Wu, Haibo Zhou, Kuikui Zhou, Henk-Jan Boele, Steven A. Kushner, Min Goo Lee, Michael J. Schmeisser, Tobias M. Boeckers, Martijn Schonewille, Freek E. Hoebeek and Chris I. De Zeeuw ()
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Saša Peter: Netherlands Institute for Neuroscience
Michiel M. ten Brinke: Erasmus MC
Jeffrey Stedehouder: Erasmus MC
Claudia M. Reinelt: Institute for Anatomy and Cell Biology, Ulm University
Bin Wu: Erasmus MC
Haibo Zhou: Erasmus MC
Kuikui Zhou: Erasmus MC
Henk-Jan Boele: Erasmus MC
Steven A. Kushner: Erasmus MC
Min Goo Lee: Yonsei University College of Medicine
Michael J. Schmeisser: Institute for Anatomy and Cell Biology, Ulm University
Tobias M. Boeckers: Institute for Anatomy and Cell Biology, Ulm University
Martijn Schonewille: Erasmus MC
Freek E. Hoebeek: Erasmus MC
Chris I. De Zeeuw: Netherlands Institute for Neuroscience

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12627

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DOI: 10.1038/ncomms12627

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