Altered Serotonin, Dopamine and Norepinepherine Levels in 15q Duplication and Angelman Syndrome Mouse Models

Farook, M. Febin; DeCuypere, Michael; Hyland, Keith; Takumi, Toru; LeDoux, Mark S.; Reiter, Lawrence T.

doi:10.1371/journal.pone.0043030

Cited by 41 publications

(31 citation statements)

References 53 publications

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“…Notably, a recent study showed that AS mice exhibited behavioral deficits that correlated with abnormal dopamine signaling (47). Specifically, AS mice exhibited changes in dopamine release in both the mesolimbic and nigrostriatal pathways (47), whereas another study reported increased dopamine levels in the striatum, midbrain, and frontal cortex of AS mice (48). AS mice were also shown to have a reduced number of tyrosine hydroxylase-positive neurons in the substantia nigra (10).…”

Section: Discussionmentioning

confidence: 99%

Dissociation of locomotor and cerebellar deficits in a murine Angelman syndrome model

Bruinsma¹,

Schonewille²,

Gao³

et al. 2015

Journal of Clinical Investigation

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Section: Discussionmentioning

confidence: 99%

Dissociation of locomotor and cerebellar deficits in a murine Angelman syndrome model

Bruinsma¹,

Schonewille²,

Gao³

et al. 2015

Journal of Clinical Investigation

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“…Mouse models of 15q11-q13 duplication and Smith-Lemli-Opitz syndromes show alterations in the central 5-HT system (Waage-Baudet et al, 2003, Nakatani et al, 2009, Farook et al, 2012, Korade et al, 2013). The BTBR inbred mouse strain, which shows many autism-relevant behavioral phenotypes, shows decreased baseline SERT binding throughout the brain and increased 5-HT 1A activity in the hippocampus (Gould et al, 2011, Gould et al, 2014).…”

Section: Mouse Models Of Asd Risk With Abnormal 5-htmentioning

confidence: 99%

The serotonin system in autism spectrum disorder: From biomarker to animal models

2016

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Elevated whole blood serotonin, or hyperserotonemia, was the first biomarker identified in autism spectrum disorder (ASD) and is present in more than 25% of affected children. The serotonin system is a logical candidate for involvement in ASD due to its pleiotropic role across multiple brain systems both dynamically and across development. Tantalizing clues connect this peripheral biomarker with changes in brain and behavior in ASD, but the contribution of the serotonin system to ASD pathophysiology remains incompletely understood. Studies of whole blood serotonin levels in ASD and in a large founder population indicate greater heritability than for the disorder itself and suggest an association with recurrence risk. Emerging data from both neuroimaging and postmortem samples also indicate changes in the brain serotonin system in ASD. Genetic linkage and association studies of both whole blood serotonin levels and of ASD risk point to the chromosomal region containing the serotonin transporter (SERT) gene in males but not in females. In ASD families with evidence of linkage to this region, multiple rare SERT amino acid variants lead to a convergent increase in serotonin uptake in cell models. A knock-in mouse model of one of these variants, SERT Gly56Ala, recapitulates the hyperserotonemia biomarker and shows increased brain serotonin clearance, increased serotonin receptor sensitivity, and altered social, communication, and repetitive behaviors. Data from other rodent models also suggest an important role for the serotonin system in social behavior, in cognitive flexibility, and in sensory development. Recent work indicates that reciprocal interactions between serotonin and other systems, such as oxytocin, may be particularly important for social behavior. Collectively, these data point to the serotonin system as a prime candidate for treatment development in a subgroup of children defined by a robust, heritable biomarker.

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“…The transmitting grandmother was found in standardized assessments of adult ADHD traits to be above the 95th percentile for impulsivity traits. Recently, Bowton et al described the transmission of the DAT Val559 variant to two, unrelated male subjects with ASD (49) that was not seen in matched unaffected subjects, extending the possible disease associations to a third disorder with evidence of DA signaling perturbations (50)(51)(52)(53)(54)(55)(56)(57).…”

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confidence: 99%

The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants

Mergy¹,

Gowrishankar²,

Gresch

et al. 2014

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

113

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Despite the critical role of the presynaptic dopamine (DA) transporter (DAT, SLC6A3) in DA clearance and psychostimulant responses, evidence that DAT dysfunction supports risk for mental illness is indirect. Recently, we identified a rare, nonsynonymous Slc6a3 variant that produces the DAT substitution Ala559Val in two male siblings who share a diagnosis of attention-deficit hyperactivity disorder (ADHD), with other studies identifying the variant in subjects with bipolar disorder (BPD) and autism spectrum disorder (ASD). Previously, using transfected cell studies, we observed that although DAT Val559 displays normal total and surface DAT protein levels, and normal DA recognition and uptake, the variant transporter exhibits anomalous DA efflux (ADE) and lacks capacity for amphetamine (AMPH)-stimulated DA release. To pursue the significance of these findings in vivo, we engineered DAT Val559 knock-in mice, and here we demonstrate in this model the presence of elevated extracellular DA levels, altered somatodendritic and presynaptic D2 DA receptor (D2R) function, a blunted ability of DA terminals to support depolarization and AMPHevoked DA release, and disruptions in basal and psychostimulant-evoked locomotor behavior. Together, our studies demonstrate an in vivo functional impact of the DAT Val559 variant, providing support for the ability of DAT dysfunction to impact risk for mental illness.T he neurotransmitter dopamine (DA) plays a key role in regulating brain circuits that control reward, attention, and locomotor activity (1-3), Accordingly, dopaminergic dysfunction is believed to contribute to several neuropsychiatric disorders including Parkinson's disease (4), bipolar disorder (BPD) (5), drug abuse and addiction (6), and attention-deficit hyperactivity disorder (ADHD) (7,8). The presynaptic DA transporter (DAT) is the primary mechanism for terminating DA signaling at the synapse (9) and is the primary target for several psychostimulant drugs including cocaine (COC), methylphenidate (MPH), and amphetamine (AMPH). COC and MPH are DAT antagonists, elevating extracellular DA levels by preventing DAT-mediated DA reuptake (10). AMPH actions are more complex (11). AMPH is structurally similar to DA and, as a result, is transported by DAT, competing with DA during the reuptake process. AMPH also induces DAT-mediated nonvesicular release, also termed "DA efflux," a process that involves the actions of intracellular signaling proteins such as CamKIIα (12-16) and , alterations in interactions with DAT-associated proteins and phospholipids (12,14,20), and changes in DAT phosphorylation (12,16,(21)(22)(23)) that biases the transporter toward an efflux-competent mechanism. Despite their mechanistic differences, MPH and AMPH both rapidly elevate DA in the CNS and are components of the most frequently prescribed medications for ADHD, Ritalin and Adderall, respectively. The DA modulatory actions of MPH and AMPH reinforce hypotheses derived from brain imaging studies (24) and the analysis of common genetic variation (25-30)...

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Altered Serotonin, Dopamine and Norepinepherine Levels in 15q Duplication and Angelman Syndrome Mouse Models

Cited by 41 publications

References 53 publications

Dissociation of locomotor and cerebellar deficits in a murine Angelman syndrome model

Dissociation of locomotor and cerebellar deficits in a murine Angelman syndrome model

The serotonin system in autism spectrum disorder: From biomarker to animal models

The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants

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