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  • 1
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    Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-07-06
    Description: 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3615424/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3615424/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tsai, Peter T -- Hull, Court -- Chu, YunXiang -- Greene-Colozzi, Emily -- Sadowski, Abbey R -- Leech, Jarrett M -- Steinberg, Jason -- Crawley, Jacqueline N -- Regehr, Wade G -- Sahin, Mustafa -- K12 NS079414/NS/NINDS NIH HHS/ -- P30HD18655/HD/NICHD NIH HHS/ -- R01 NS032405/NS/NINDS NIH HHS/ -- R01NS032405/NS/NINDS NIH HHS/ -- R01NS58956/NS/NINDS NIH HHS/ -- T32 MH020017/MH/NIMH NIH HHS/ -- T32 NS007473/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- Intramural NIH HHS/ -- England -- Nature. 2012 Aug 30;488(7413):647-51. doi: 10.1038/nature11310.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. peter.tsai@childrens.harvard.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22763451" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autistic Disorder/complications/genetics/pathology/*physiopathology ; Behavior, Animal/drug effects ; Cell Count ; Cell Shape/drug effects ; Cerebellum/drug effects/pathology/*physiopathology ; Grooming/drug effects/physiology ; Heterozygote ; Maze Learning/drug effects/physiology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mutation/genetics ; Purkinje Cells/drug effects/*metabolism ; Rotarod Performance Test ; Sirolimus/pharmacology ; Synapses/metabolism ; TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism ; Tuberous Sclerosis/complications/genetics ; Tumor Suppressor Proteins/deficiency/*genetics/*metabolism ; Vocalization, Animal/drug effects/physiology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    The calcium sensor synaptotagmin 7 is required for synaptic facilitation (2016)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2016-01-08
    Description: It has been known for more than 70 years that synaptic strength is dynamically regulated in a use-dependent manner. At synapses with a low initial release probability, closely spaced presynaptic action potentials can result in facilitation, a short-term form of enhancement in which each subsequent action potential evokes greater neurotransmitter release. Facilitation can enhance neurotransmitter release considerably and can profoundly influence information transfer across synapses, but the underlying mechanism remains a mystery. One proposed mechanism is that a specialized calcium sensor for facilitation transiently increases the probability of release, and this sensor is distinct from the fast sensors that mediate rapid neurotransmitter release. Yet such a sensor has never been identified, and its very existence has been disputed. Here we show that synaptotagmin 7 (Syt7) is a calcium sensor that is required for facilitation at several central synapses. In Syt7-knockout mice, facilitation is eliminated even though the initial probability of release and the presynaptic residual calcium signals are unaltered. Expression of wild-type Syt7 in presynaptic neurons restored facilitation, whereas expression of a mutated Syt7 with a calcium-insensitive C2A domain did not. By revealing the role of Syt7 in synaptic facilitation, these results resolve a longstanding debate about a widespread form of short-term plasticity, and will enable future studies that may lead to a deeper understanding of the functional importance of facilitation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4729191/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4729191/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jackman, Skyler L -- Turecek, Josef -- Belinsky, Justine E -- Regehr, Wade G -- NS032405/NS/NINDS NIH HHS/ -- P30 NS072030/NS/NINDS NIH HHS/ -- R01 NS032405/NS/NINDS NIH HHS/ -- England -- Nature. 2016 Jan 7;529(7584):88-91. doi: 10.1038/nature16507.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26738595" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Calcium/*metabolism ; Calcium Signaling ; Female ; Male ; Mice ; Mice, Knockout ; Neuronal Plasticity ; Neurons/metabolism/secretion ; Neurotransmitter Agents/*secretion ; Presynaptic Terminals/metabolism ; Synapses/*metabolism/secretion ; *Synaptic Transmission ; Synaptotagmins/deficiency/genetics/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
    Electronic Resource
    Electronic Resource
    TIMING OF SYNAPTIC TRANSMISSION (1999)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 61 (1999), S. 521-542 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Abstract Many behaviors require rapid and precisely timed synaptic transmission. These include the determination of a sound's direction by detecting small interaural time differences and visual processing, which relies on synchronous activation of large populations of neurons. In addition, throughout the brain, concerted firing is required by Hebbian learning mechanisms, and local circuits are recruited rapidly by fast synaptic transmission. To achieve speed and precision, synapses must optimize the many steps between the firing of a presynaptic cell and the response of its postsynaptic targets. Until recently, the behavior of mammalian synapses at physiological temperatures was primarily extrapolated from studies at room temperature or from the properties of invertebrate synapses. Recent studies have revealed some of the specializations that make synapses fast and precise in the mammalian central nervous system at physiological temperatures.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.61.1.521
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    Paper (German National Licenses)
    Fulltext
  • 4
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    Sodium action potentials in the dendrites of cerebellar Purkinje cells. (1992)
    National Academy of Sciences
    Details
    Publication Date: 1992-06-15
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 5
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    TIMING OF SYNAPTIC TRANSMISSION (1999)
    Annual Reviews
    Details
    Publication Date: 1999-03-01
    Description: ▪ Abstract  Many behaviors require rapid and precisely timed synaptic transmission. These include the determination of a sound's direction by detecting small interaural time differences and visual processing, which relies on synchronous activation of large populations of neurons. In addition, throughout the brain, concerted firing is required by Hebbian learning mechanisms, and local circuits are recruited rapidly by fast synaptic transmission. To achieve speed and precision, synapses must optimize the many steps between the firing of a presynaptic cell and the response of its postsynaptic targets. Until recently, the behavior of mammalian synapses at physiological temperatures was primarily extrapolated from studies at room temperature or from the properties of invertebrate synapses. Recent studies have revealed some of the specializations that make synapses fast and precise in the mammalian central nervous system at physiological temperatures.
    Print ISSN: 0066-4278
    Electronic ISSN: 1545-1585
    Topics: Biology , Medicine
    Published by Annual Reviews
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