Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature (Lond)

The F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature (Impact Factor: 41.46). 07/2012; 488(7413):647-51. DOI: 10.1038/nature11310
Source: PubMed


Autism spectrum disorders (ASDs) are highly prevalent neurodevelopmental disorders, but the underlying pathogenesis remains poorly understood. Recent studies have implicated the cerebellum in these disorders, with post-mortem studies in ASD patients showing cerebellar Purkinje cell (PC) loss, and isolated cerebellar injury has been associated with a higher incidence of ASDs. However, the extent of cerebellar contribution to the pathogenesis of ASDs remains unclear. Tuberous sclerosis complex (TSC) is a genetic disorder with high rates of comorbid ASDs that result from mutation of either TSC1 or TSC2, whose protein products dimerize and negatively regulate mammalian target of rapamycin (mTOR) signalling. TSC is an intriguing model to investigate the cerebellar contribution to the underlying pathogenesis of ASDs, as recent studies in TSC patients demonstrate cerebellar pathology and correlate cerebellar pathology with increased ASD symptomatology. Functional imaging also shows that TSC patients with ASDs display hypermetabolism in deep cerebellar structures, compared to TSC patients without ASDs. However, the roles of Tsc1 and the sequelae of Tsc1 dysfunction in the cerebellum have not been investigated so far. Here we show that both heterozygous and homozygous loss of Tsc1 in mouse cerebellar PCs results in autistic-like behaviours, including abnormal social interaction, repetitive behaviour and vocalizations, in addition to decreased PC excitability. Treatment of mutant mice with the mTOR inhibitor, rapamycin, prevented the pathological and behavioural deficits. These findings demonstrate new roles for Tsc1 in PC function and define a molecular basis for a cerebellar contribution to cognitive disorders such as autism.

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Available from: Mustafa Sahin, Jul 23, 2015
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    • "We first determined the degree of migration delay caused by Tsc2 KD. We used in utero electroporation to introduce Tsc2 shRNA (Tsai et al., 2012) or control scrambled shRNA along with pCAG-GFP to cortical progenitors at E13.5 and E16.5, and we analyzed the position of GFP+ neurons 5 days later (Figures S6C and 6A). Similar to the delayed migration in Tsc2 CKO shown in Figure 1F, significantly fewer Tsc2 KD late-born neurons reached the top of the cortex compared to control (Figure 6A). "
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    ABSTRACT: Tuberous sclerosis complex (TSC) is associated with neurodevelopmental abnormalities, including defects in neuronal migration. However, the alterations in cell signaling mechanisms critical for migration and final positioning of neurons in TSC remain unclear. Our detailed cellular analyses reveal that reduced Tsc2 in newborn neurons causes abnormalities in leading processes of migrating neurons, accompanied by significantly delayed migration. Importantly, we demonstrate that Reelin-Dab1 signaling is aberrantly regulated in TSC mouse models and in cortical tubers from TSC patients owing to enhanced expression of the E3 ubiquitin ligase Cul5, a known mediator of pDab1 ubiquitination. Likewise, mTORC1 activation by Rheb overexpression generates similar neuronal and Reelin-Dab1 signaling defects, and directly upregulates Cul5 expression. Inhibition of mTORC1 by rapamycin treatment or by reducing Cul5 largely restores normal leading processes and positioning of migrating neurons. Thus, disrupted Reelin-Dab1 signaling is critically involved in the neuronal migration defects of TSC. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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    • "Corrects deficits in memory/learning (Morris water maze and the 8-arm radial maze) and contextual discrimination. Ehninger et al. (2008) THC-cannabinoid treatment Pre-treatment for 5 days Prevented decline in performance on the novel object recognition test Puighermanal et al. (2009) Alcohol addiction 1 dose Attenuates conditioned preference to alcohol, e.g., decreased binge drinking and motivation to consume alcohol Neasta et al. (2010) Deletion of Tsc1 in the cerebellar Purkinje cells Started at P7 Prevented deficits in cognition on the water T-maze, pathological phenotypes of autism in the brain, and autistic-like behavior Tsai et al. (2012) Pilocarpine-induced seizures Post-treatment every other day for 8 days "
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    ABSTRACT: The discovery that rapamycin increases lifespan in mice and restores/delays many aging phenotypes has led to the speculation that rapamycin has 'anti-aging' properties. The major question discussed in this review is whether a manipulation that has anti-aging properties can alter the onset and/or progression of Alzheimer's disease, a disease in which age is the major risk factor. Rapamycin has been shown to prevent (and possibly restore in some cases) the deficit in memory observed in the mouse model of Alzheimer's disease (AD-Tg) as well as reduce Aβ and tau aggregation, restore cerebral blood flow and vascularization, and reduce microglia activation. All of these parameters are widely recognized as symptoms central to the development of AD. Furthermore, rapamycin has also been shown to improve memory and reduce anxiety and depression in several other mouse models that show cognitive deficits as well as in 'normal' mice. The current research shows the feasibility of using pharmacological agents that increase lifespan, such as those identified by the National Institute on Aging Intervention Testing Program, to treat Alzheimer's disease. Copyright © 2014. Published by Elsevier Inc.
    Full-text · Article · Dec 2014 · Experimental Gerontology
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    • "The highly complex and enlarged dentate nucleus in humans shows a pronounced left-right asymmetry (Baizer, 2014) and, correspondingly, consistent unilateral reduction in dentate projections is inferred from a study of individuals with Asperger's (Catani et al., 2008). Finally, a recent transgenic study in which mutation of the tuberous sclerosis gene associated with human ASD was targeted specifically to Purkinje cells resulted in an ASD-like mouse phenotype (Tsai et al., 2012). Collectively, these observations suggest that, by virtue of cortico-cerebellar connectivity, selective cerebellar cell loss can mimic the effects of what are more readily perceived as 'cortical' syndromes (Schmahmann and Pandya, 2008). "
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    ABSTRACT: The cerebellum is a pre-eminent model for the study of neurogenesis and circuit assembly. Increasing interest in the cerebellum as a participant in higher cognitive processes and as a locus for a range of disorders and diseases make this simple yet elusive structure an important model in a number of fields. In recent years, our understanding of some of the more familiar aspects of cerebellar growth, such as its territorial allocation and the origin of its various cell types, has undergone major recalibration. Furthermore, owing to its stereotyped circuitry across a range of species, insights from a variety of species have contributed to an increasingly rich picture of how this system develops. Here, we review these recent advances and explore three distinct aspects of cerebellar development - allocation of the cerebellar anlage, the significance of transit amplification and the generation of neuronal diversity - each defined by distinct regulatory mechanisms and each with special significance for health and disease.
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