Imaging genetics in obsessive-compulsive disorder: Linking genetic variations to alterations in neuroimaging

Grünblatt, Edna; Hauser, Tobias U.; Walitza, Susanne

doi:10.1016/j.pneurobio.2014.07.003

Cited by 31 publications

(22 citation statements)

References 105 publications

(143 reference statements)

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“…Humans lacking EAAT3 develop dicarboxylic aminoaciduria in agreement with the studies on mice (Bailey et al, 2011), and human EAAT3 polymorphisms have been reported to be associated with obsessive-compulsive disorders (Brandl et al, 2012;Walitza et al, 2010;Grunblatt et al, 2014).…”

Section: A C C E P T E D Accepted Manuscriptsupporting

confidence: 78%

Neuronal vs glial glutamate uptake: Resolving the conundrum

Danbolt

Furness

Zhou

2016

Neurochemistry International

169

143

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Neither normal brain function nor the pathological processes involved in neurological diseases can be adequately understood without knowledge of the release, uptake and metabolism of glutamate. The reason for this is that glutamate (a) is the most abundant amino acid in the brain, (b) is at the cross-roads between several metabolic pathways, and (c) serves as the major excitatory neurotransmitter. In fact most brain cells express glutamate receptors and are thereby influenced by extracellular glutamate. In agreement, brain cells have powerful uptake systems that constantly remove glutamate from the extracellular fluid and thereby limit receptor activation. It has been clear since the 1970s that both astrocytes and neurons express glutamate transporters. However, the relative contribution of neuronal and glial transporters to the total glutamate uptake activity, however, as well as their functional importance, has been hotly debated ever since. The present short review provides (a) an overview of what we know about neuronal glutamate uptake as well as an historical description of how we got there, and (b) a hypothesis reconciling apparently contradicting observations thereby possibly resolving the paradox. ABBREVIATIONSCre, Cyclization recombinase (Le and Sauer, 2000); EAAC1, glutamate transporter (EAAT3; slc1a1; Kanai and Hediger, 1992; Bjørås et al., 1996); EAAT, excitatory amino acid transporter (synonym to glutamate transporter); GABA, γ-aminobutyric acid; GLAST, rat glutamate transporter (EAAT1; slc1a3; Storck et al., 1992;Tanaka, 1993a); GLT-1, rat glutamate transporter (EAAT2; slc1a2; Pines et al., 1992); GLUL, glutamine synthetase; TBOA, DL-threo-β-benzyloxyaspartate AbstractNeither normal brain function nor the pathological processes involved in neurological diseases can be adequately understood without knowledge of the release, uptake and metabolism of glutamate. The reason for this is that glutamate (a) is the most abundant amino acid in the brain, (b) is at the cross-roads between several metabolic pathways, and (c) serves as the major excitatory neurotransmitter. In fact most brain cells express glutamate receptors and are thereby influenced by extracellular glutamate. In agreement, brain cells have powerful uptake systems that constantly remove glutamate from the extracellular fluid and thereby limit receptor activation. It has been clear since the 1970s that astrocytes and neurons express glutamate transporters. The relative contribution of neuronal and glial transporters to the total glutamate uptake activity, however, as well as their functional importance, has been hotly debated ever since. The present short review provides (a) an overview of what we know about neuronal glutamate uptake as well as an historical description of how we got there, and (b) an hypothesis reconciling apparently contradicting observations thereby possibly resolving the paradox.

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Section: A C C E P T E D Accepted Manuscriptsupporting

confidence: 78%

Neuronal vs glial glutamate uptake: Resolving the conundrum

Danbolt

Furness

Zhou

2016

Neurochemistry International

169

143

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“…A thorough coverage of the complex interplay between different neurotransmitter systems, environmental factors and other risk factors is outside the scope of this review. For further reading into this, we will refer to some excellent reviews (Murphy et al, 2013, Bokor and Anderson, 2014, Grunblatt et al, 2014, Pauls et al, 2014, Wood and Ahmari, 2015). Instead we will focus on the evidence of a functional role of EAAT3 perturbations in OCD.…”

Section: Eaat3 In Diseasementioning

confidence: 99%

The importance of the excitatory amino acid transporter 3 (EAAT3)

Bjørn‐Yoshimoto

Underhill

2016

Neurochemistry International

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The neuronal excitatory amino acid transporter 3 (EAAT3) is fairly ubiquitously expressed in the brain, though it does not necessarily maintain the same function everywhere. It is important in maintaining low local concentrations of glutamate, where its predominant post-synaptic localization can buffer nearby glutamate receptors and modulate excitatory neurotransmission and synaptic plasticity. It is also the main neuronal cysteine uptake system acting as the rate-limiting factor for the synthesis of glutathione, a potent antioxidant, in EAAT3 expressing neurons, while on GABAergic neurons, it is important in supplying glutamate as a precursor for GABA synthesis. Several diseases implicate EAAT3, and modulation of this transporter could prove a useful therapeutic approach. Regulation of EAAT3 could be targeted at several points for functional modulation, including the level of transcription, trafficking and direct pharmacological modulation, and indeed, compounds and experimental treatments have been identified that regulate EAAT3 function at different stages, which together with observations of EAAT3 regulation in patients is giving us insight into the endogenous function of this transporter, as well as the consequences of altered function. This review summarizes work done on elucidating the role and regulation of EAAT3.

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“…Although a number of neuroimaging and genetic studies have been carried out in patients with OCD, only a few have evaluated genetic and neuroanatomical variables concurrently, and DTI has, to date, not been performed in any of them (Grünblatt et al, 2014). In this study, we conducted a preliminary analysis of the association between 262 validated polymorphisms within 35 candidate gene regions related to OCD and WM microstructure, assessed by DTI, in child and adolescent OCD patients.…”

Section: Discussionmentioning

confidence: 99%

“…In this regard, neuroimaging measures of WM microstructure could serve as promising intermediate phenotypes for genetic analysis of the disorder. OCD studies in which genetic and neuroanatomical variables are evaluated concurrently are few in number and, to date, DTI has not been performed in any of them (Grünblatt et al, 2014). The objective of the present study was to explore the association between variability in genes related to the pathophysiology of OCD and altered WM microstructure previously identified in child and adolescent patients with the disease.…”

Section: Introductionmentioning

confidence: 99%