Abnormal classical eye-blink conditioning in autism

Sears, Lonnie; Finn, Peter R.; Steinmetz, Joseph E.

doi:10.1007/bf02172283

Cited by 158 publications

(189 citation statements)

References 39 publications

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“…Significantly elevated levels of these neurotransmitters in the cerebellum could cause enhanced eye-blink learning in MAO A/B KO mice. Finally, we note a study of eye-blink conditioning in autistic children (52) in which it was reported that the autistic children learned this task faster than age-matched normal control children, just as is the case for our MAO A/B KO mice. Future studies are warranted to find out the neuroanatomical abnormalities in the cerebellum in MAO A/B KO mice.…”

Section: Mao A/b Ko Mice Showed Enhanced Contextual and Cue Memory Andsupporting

confidence: 53%

Cognitive abnormalities and hippocampal alterations in monoamine oxidase A and B knockout mice

Singh

Bortolato

Bali

et al. 2013

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

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The monoamine oxidase isoenzymes (MAOs) A and B play important roles in the homeostasis of monoaminergic neurotransmitters. The combined deficiency of MAO A and B results in significantly elevated levels of serotonin (5-hydroxytryptamine), norepinephrine, dopamine, and β-phenylethylamine; in humans and mice, these neurochemical changes are accompanied by neurodevelopmental perturbations as well as autistic-like responses. Ample evidence indicates that normal levels of monoamines in the hippocampus, amygdala, frontal cortex, and cerebellum are required for the integrity of learning and memory. Thus, in the present study, the cognitive status of MAO A/B knockout (KO) mice was examined with a wide array of behavioral tests. In comparison with male wild-type littermates, MAO A/B KO mice exhibited abnormally high and overgeneralized fear conditioning and enhanced eye-blink conditioning. These alterations were accompanied by significant increases in hippocampal long-term potentiation and alterations in the relative expression of NMDA glutamate receptor subunits. Our data suggest that chronic elevations of monoamines, because of the absence of MAO A and MAO B, cause functional alterations that are accompanied with changes in the cellular mechanisms underlying learning and memory. The characteristics exhibited by MAO A/B KO mice highlight the potential of these animals as a useful tool to provide further insight into the molecular bases of disorders associated with abnormal monoaminergic profiles.adult neurogenesis | autism-spectrum disorder | cognition M onoaminergic neurotransmitters, such as serotonin (5-HT), norepinephrine (NE), and dopamine (DA), are known to play a critical role in the modulation of mood and emotion, as well as the control of motor, perceptual, and other cognitive functions (1). Abnormal levels of these monoamines have been associated with several neuropsychiatric disorders (2-5). The enzymatic metabolism of these neurotransmitters is mainly catalyzed by monoamine oxidase (MAO), a mitochondrial-bound flavoprotein (6). The two MAO isoenzymes, A and B, are encoded by different genes next to each other on the X chromosome (7), with 70% amino acid identity (8) and identical intron-exon organization (9). MAO A has a higher affinity for 5-HT, NE, and DA (6, 10). In contrast, MAO B prefers phenylethylamine (PEA) as substrate (11), although it can degrade 5-HT, NE, and DA in the absence of MAO A (12). As a consequence, the lack of both isoenzymes in mice results in significantly higher monoamine levels than those observed in single knockout (KO) counterparts (12). The deficiency of both MAO isoenzymes in humans has been found to be associated with severe intellectual and developmental disabilities, hypotonia, failure to thrive, and autisticlike symptoms (including sociocommunicative deficits and perseverative manifestations) (13-15). Although similar alterations were also featured by MAO A KO mice, the severity of the changes was typically more pervasive in MAO A/B KO mice, supporting the idea that the se...

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Section: Mao A/b Ko Mice Showed Enhanced Contextual and Cue Memory Andsupporting

confidence: 53%

Cognitive abnormalities and hippocampal alterations in monoamine oxidase A and B knockout mice

Singh

Bortolato

Bali

et al. 2013

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

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“…Among adolescents and young adults with autism (12-29 years old), an inverse correlation was found between caudate volume and ritualistic-repetitive behaviors (with and without total brain volume as a covariate), such as the presence of compulsions/rituals and difficulty changing routine (Sears et al 1994). In a somewhat older adult sample (17-55 years old) with an ASD diagnosis, a direct relationship between repetitive behaviors and right caudate volumes was noted (Hollander et al 2005).…”

Section: Introductionmentioning

confidence: 92%

“…Analysis of caudate volume in adolescents and adults indicated no differences between individuals without psychiatric diagnoses and those diagnosed with autism when a measure of total brain was controlled (Gaffney et al 1989;Hardan et al 2003;Sears et al 1999). However, significantly larger caudate volumes were found in autistic samples when total brain volume was not included (Herbert et al 2003;Sears et al 1994). The latter study used data from children ages 7-11 years, and found that different brain structures may be disproportional in size, being excessively large or small, in young autistic boys.…”

Section: Introductionmentioning

confidence: 93%

Caudate Nucleus Volume and Cognitive Performance: Are They Related in Childhood Psychopathology?

Voelbel¹,

Bates²,

Buckman³

et al. 2006

Biological Psychiatry

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Background-Impaired neuropsychological test performance, especially on tests of executive function and attention, is often seen in children diagnosed with autism spectrum disorders (ASD). Structures involved in fronto-striatal circuitry, such as the caudate nucleus, may support these cognitive abilities. However, few studies have examined caudate volumes specifically in children with ASD, or correlated caudate volumes to cognitive ability.

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“…[45][46][47][48] They also extend to the reciprocity/temporal synchrony skills required for conversation. [49][50][51][52] Objectively recorded atypical sleep architecture in young adults with high-functioning autism and Asperger syndrome 53 and in children with autistic disorder 54 shows association between sleep profiles and autistic symptomatology.…”

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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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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Abnormal classical eye-blink conditioning in autism

Cited by 158 publications

References 39 publications

Cognitive abnormalities and hippocampal alterations in monoamine oxidase A and B knockout mice

Cognitive abnormalities and hippocampal alterations in monoamine oxidase A and B knockout mice

Caudate Nucleus Volume and Cognitive Performance: Are They Related in Childhood Psychopathology?

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

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