Is autism due to brain desynchronization?

Welsh, John P.; Ahn, Edward S.; Placantonakis, Dimitris G.

doi:10.1016/j.ijdevneu.2004.09.002

Cited by 96 publications

(75 citation statements)

References 66 publications

(75 reference statements)

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“…6 The role of per1 in modulating high-frequency oscillators concerned with communicative timing, [69][70][71] together with our findings of association of per1 with autistic disorder, strengthens the notion that temporal deficits are quintessential to autistic disorder. [21][22][23][24][25][26]28,29,39 Purkinje neurons are important for learning appropriate timing 120,121 and their abnormally low number in the cerebella of autistic subjects 115,122 is considered a keystone biological observation implicating cerebellar dysfunction. 123,124 In this context, reports of a per1 interacting protein (PIPS) in rat that co-translocates with per1 into the nucleus 125 and which is further shown to be required for neuronal growth factor-mediated neuronal survival in P12 cells, 126 tentatively suggests a role for per1 in the lack of Purkinje neurons of the cerebellum in autism.…”

Section: Discussionmentioning

confidence: 99%

“…Newson 22 ), with hypotheses encompassing circadian, communicative and/or neurological aspects of timing. 21,[23][24][25][26][27][28][29] For example, Boucher 25 suggests a core timing deficit presenting different manifestations by its effect on the elements of an integrated system of neural and physiological oscillators. Wimpory et al 21 hypothesize a causative, concurrent and developmental role 30 for timing deficit in autistic disorder and that this deficit is derived from pathological variations in the structure/ function of clock/clock-related genes.…”

Section: Timing Difficulties and Autismmentioning

confidence: 99%

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Association of Per1 and Npas2 with autistic disorder: support for the clock genes/social timing hypothesis

et al. 2007

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4Specialist Children's Services, North West Wales NHS Trust, Bangor, UK Clock gene anomalies have been suggested as causative factors in autism. We screened eleven clock/clock-related genes in a predominantly high-functioning Autism Genetic Resource Exchange sample of strictly diagnosed autistic disorder progeny and their parents (110 trios) for association of clock gene variants with autistic disorder. We found significant association (P < 0.05) for two single-nucleotide polymorphisms in per1 and two in npas2. Analysis of all possible combinations of two-marker haplotypes for each gene showed that in npas2 40 out of the 136 possible two-marker combinations were significant at the P < 0.05 level, with the best result between markers rs1811399 and rs2117714, P = 0.001. Haplotype analysis within per1 gave a single significant result: a global P = 0.027 for the markers rs2253820-rs885747. No two-marker haplotype was significant in any of the other genes, despite the large number of tests performed. Our findings support the hypothesis that these epistatic clock genes may be involved in the etiology of autistic disorder. Problems in sleep, memory and timing are all characteristics of autistic disorder and aspects of sleep, memory and timing are each clock-gene-regulated in other species. We identify how our findings may be relevant to theories of autism that focus on the amygdala, cerebellum, memory and temporal deficits. We outline possible implications of these findings for developmental models of autism involving temporal synchrony/social timing.

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Section: Discussionmentioning

confidence: 99%

Section: Timing Difficulties and Autismmentioning

confidence: 99%

Association of Per1 and Npas2 with autistic disorder: support for the clock genes/social timing hypothesis

et al. 2007

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“…In a paradigm of operant conditioning, it was found that distributed activity among subsets of 20-30 CFs was phase-locked to a rhythmic movement at Ϸ7 Hz (30). We have recently suggested that an evoked oscillation through the CF system may scale a CS-US interval into units of motor time to optimize the learned timing and expression of a movement during classical conditioning (31). Further experiments are warranted.…”

Section: Discussionmentioning

confidence: 99%

Normal motor learning during pharmacological prevention of Purkinje cell long-term depression

Welsh

Yamaguchi

Zeng

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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130

105

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Systemic delivery of (1R-1-benzo thiophen-5-yl-2[2-diethylamino)-ethoxy] ethanol hydrochloride (T-588) prevented long-term depression (LTD) of the parallel fiber (PF)-Purkinje cell (PC) synapse induced by conjunctive climbing fiber and PF stimulation in vivo.However, similar concentrations of T-588 in the brains of behaving mice and rats affected neither motor learning in the rotorod test nor the learning of motor timing during classical conditioning of the eyeblink reflex. Rats given doses of T-588 that prevented PF-PC LTD were as proficient as controls in learning to adapt the timing of their conditioned eyeblink response to a 150-or 350-ms change in the timing of the paradigm. The experiment indicates that PF-PC LTD under control of the climbing fibers is not required for general motor adaptation or the learning of response timing in two common models of motor learning for which the cerebellum has been implicated. Alternative mechanisms for motor timing and possible functions for LTD in protection from excitotoxicity are discussed.cerebellum ͉ eyeblink ͉ field potentials ͉ rotorod A longstanding hypothesis concerning cerebellar function has been the proposal that it serves as the repository for new motor skills through plasticity of the parallel fiber (PF)-Purkinje cell (PC) synapse (1, 2). In the prevailing hypothesis of ''cerebellar learning,'' the acquisition of new skills is controlled by climbing fibers (CFs), which function to depress the strength of the PF-PC synapse when the two afferents are conjointly active. The cerebellar learning hypothesis has inspired much research since the demonstration, in vivo, that near-synchronous activation of CFs and PFs by direct electrical stimulation depressed the strength of the excitatory potentials triggered by PFs in PCs (3). Because the depression required repeated pairings of CF and PF synaptic input and was retained for many hours, the phenomenon has been termed cerebellar long-term depression (LTD) and has been invoked to explain the acquisition and lifetime retention of many motor skills, including learned motor timing, reflex adaptation, and procedural and implicit learning (4).A substantial body of evidence has established the necessary intracellular events that produce PC LTD in vitro, and these events have been assumed to relate to motor learning in vivo. Moreover, a recent experiment showed that mouse PCs genetically modified to lack protein kinase C (PKC) function could not undergo LTD (5, 6); when such transgenic mice were tested in classical eyeblink conditioning, they were unable to learn the appropriate motor timing of conditioned eyeblinks [conditioned response (CR)] (7). That finding, complemented by the finding that cerebellar decortication also impaired the learned motor timing of CRs (8), has sustained the hypothesis that PF-PC LTD is required for motor learning. However, it is also evident that, up to this time, it has not been determined whether LTD occurs in awake animals as they acquire and retain new motor skills. Thus, it has been diffic...

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“…However, it has also been suggested that timing of fast movement and modulation of cerebellar output during movement is accomplished by rhythmic and synchronized firing of ensembles of olivary neurons and their population code rather than individual neuronal oscillations (Welsh et al, 1995;Welsh, 2002). Welsh et al (2005) further hypothesized that disorders such as autism may be explained by inferior olive dysfunction resulting in impairment of temporal processing and reaction to fast sensory input.…”

Section: Introductionmentioning

confidence: 99%

Role of the Olivo-Cerebellar System in Timing

Xu¹,

Liu²,

Ashe³

et al. 2006

J. Neurosci.

107

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Timing has been proposed as a basic function of the cerebellar cortex (particularly the climbing fiber afferents and their sole source, the inferior olive) that explains the contribution of the cerebellum to both motor control and nonmotor cognitive functions. However, whether the olivo-cerebellar system mediates time perception without motor behavior remains controversial. We used event-related functional magnetic resonance imaging to dissociate the neural correlates of the perceptual from the motor aspects of timing. The results show activation of multiple areas within the cerebellar cortex during both perception and motor performance of temporal sequences. The results further show that the inferior olive was activated only when subjects perceived the temporal sequences without motor activity. This finding is most consistent with electrophysiological studies showing decreased responsiveness of the inferior olivary neurons to sensory input during expected, self-produced movement. Our results suggest that the primary role of the inferior olive and the climbing fiber system in timing is the encoding of temporal information independent of motor behavior.

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Is autism due to brain desynchronization?

Cited by 96 publications

References 66 publications

Association of Per1 and Npas2 with autistic disorder: support for the clock genes/social timing hypothesis

Association of Per1 and Npas2 with autistic disorder: support for the clock genes/social timing hypothesis

Normal motor learning during pharmacological prevention of Purkinje cell long-term depression

Role of the Olivo-Cerebellar System in Timing

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