Variation in SLC1A1 is related to combat-related posttraumatic stress disorder

Zhang, Jingmei; Sheerin, Christina M.; Mandel, Howard; Banducci, Anne N.; Myrick, Hugh; Acierno, Ron; Amstadter, Ananda B.; Wang, Zhewu

doi:10.1016/j.janxdis.2014.09.013

Cited by 9 publications

(11 citation statements)

References 39 publications

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“…Among OCD positional candidate genes, SLC1A1 has among the strongest support for its association with this disorder [ 78 – 84 ]. Additionally, variations in SLC1A1 gene have also been associated with other forms of anxiety disorders, including posttraumatic stress disorder (PTSD) or anxiety symptom severity in autism spectrum disorder (ASD) [ 85 , 86 ]. Thus, our observation of anxiety-like phenotype of Slc1a1 +/- mice further supports the association of this gene with anxiety and its potential comorbidity with schizophrenia.…”

Section: Discussionmentioning

confidence: 99%

Reduced Slc1a1 expression is associated with neuroinflammation and impaired sensorimotor gating and cognitive performance in mice: Implications for schizophrenia

2017

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We previously reported a 84-Kb hemi-deletion copy number variant at the SLC1A1 gene locus that reduces its expression and appeared causally linked to schizophrenia. In this report, we characterize the in vivo and in vitro consequences of reduced expression of Slc1a1 in mice. Heterozygous (HET) Slc1a1+/- mice, which more closely model the hemi-deletion we found in human subjects, were examined in a series of behavioral, anatomical and biochemical assays. Knockout (KO) mice were also included in the behavioral studies for comparative purposes. Both HET and KO mice exhibited evidence of increased anxiety-like behavior, impaired working memory, decreased exploratory activity and impaired sensorimotor gating, but no changes in overall locomotor activity. The magnitude of changes was approximately equivalent in the HET and KO mice suggesting a dominant effect of the haploinsufficiency. Behavioral changes in the HET mice were accompanied by reduced thickness of the dorsomedial prefrontal cortex. Whole transcriptome RNA-Seq analysis detected expression changes of genes and pathways involved in cytokine signaling and synaptic functions in both brain and blood. Moreover, the brains of Slc1a1+/- mice displayed elevated levels of oxidized glutathione, a trend for increased oxidative DNA damage, and significantly increased levels of cytokines. This latter finding was further supported by SLC1A1 knockdown and overexpression studies in differentiated human neuroblastoma cells, which led to decreased or increased cytokine expression, respectively. Taken together, our results suggest that partial loss of the Slc1a1 gene in mice causes haploinsufficiency associated with behavioral, histological and biochemical changes that reflect an altered redox state and may promote the expression of behavioral features and inflammatory states consistent with those observed in schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Reduced Slc1a1 expression is associated with neuroinflammation and impaired sensorimotor gating and cognitive performance in mice: Implications for schizophrenia

2017

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“…In adolescents with PTSD, significantly lower glutamate+glutamine (Glx) levels in the rostral ACC were reported in PTSD relative to HC, as well as in those with remitted symptoms relative to HC [36]. Finally, one candidate gene study explored variation in a glutamate transporter gene (SLC1A1), which codes for the excitatory amino acid transporter 3 (EAAT3) and excitatory amino acid carrier 1 (EAAC1), known to play a key role in regulating extrasynaptic glutamate concentrations [37]. Variation in SLC1A1 is hypothesized to be correlated with heightened risk for developing PTSD and greater symptom severity [37].…”

Section: Direct Evidence Of Gabaergic and Glutamatergic Abnormalitiesmentioning

confidence: 99%

“…Finally, one candidate gene study explored variation in a glutamate transporter gene (SLC1A1), which codes for the excitatory amino acid transporter 3 (EAAT3) and excitatory amino acid carrier 1 (EAAC1), known to play a key role in regulating extrasynaptic glutamate concentrations [37]. Variation in SLC1A1 is hypothesized to be correlated with heightened risk for developing PTSD and greater symptom severity [37]. They found increased likelihood of PTSD in carriers of allele rs10739062 (a single nucleotide polymorphism or “SNP” of SLC1A1), and though not statistically significant, this allele trended toward a significant association with symptom severity scores [37].…”

Section: Direct Evidence Of Gabaergic and Glutamatergic Abnormalitiesmentioning

confidence: 99%

“…Variation in SLC1A1 is hypothesized to be correlated with heightened risk for developing PTSD and greater symptom severity [37]. They found increased likelihood of PTSD in carriers of allele rs10739062 (a single nucleotide polymorphism or “SNP” of SLC1A1), and though not statistically significant, this allele trended toward a significant association with symptom severity scores [37]. …”

Section: Direct Evidence Of Gabaergic and Glutamatergic Abnormalitiesmentioning

confidence: 99%

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Glutamate dysregulation and glutamatergic therapeutics for PTSD: Evidence from human studies

Averill

Purohit²,

Averill³

et al. 2017

Neuroscience Letters

154

104

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Posttraumatic stress disorder (PTSD) is a chronic and debilitating psychiatric disorder afflicting millions of individuals across the world. While the availability of robust pharmacologic interventions is quite lacking, our understanding of the putative neurobiological underpinnings of PTSD has significantly increased over the past two decades. Accumulating evidence demonstrates aberrant glutamatergic function in mood, anxiety, and trauma-related disorders and dysfunction in glutamate neurotransmission is increasingly considered a cardinal feature of stress-related psychiatric disorders including PTSD. As part of a PTSD Special Issue, this mini-review provides a concise discussion of (1) evidence of glutamatergic abnormalities in PTSD, with emphasis on human subjects data; (2) glutamate-modulating agents as potential alternative pharmacologic treatments for PTSD; and (3) selected gaps in the literature and related future directions.

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“…39 Conversely, among individuals with pharmacoresistent neocortical epilepsy, EAAT3 expression was decreased in epileptic regions. 40 Multiple candidate gene studies report SLC1A1 genetic variation associated with psychiatric conditions including posttraumatic stress disorder, 41 autism spectrum disorder, 42 and schizophrenia. 18 The most data regarding human SLC1A1 genetic variation and psychiatric disorders are reported with obsessive-compulsive disorder (OCD).…”

Section: Discussionmentioning

confidence: 99%

Genetic variation in neuronal glutamate transport genes and associations with posttraumatic seizure

et al. 2016

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Objective Post-traumatic seizures (PTS) commonly occur following severe traumatic brain injury (sTBI). Risk factors for PTS have been identified, but variability in who develops PTS remains. Excitotoxicity may influence epileptogenesis following sTBI. Glutamate transporters manage glutamate levels and excitatory neurotransmission, and they have been associated with both epilepsy and TBI. Therefore, we aimed to determine if genetic variation in neuronal glutamate transporter genes is associated with accelerated epileptogenesis and increased PTS risk after sTBI. Methods Individuals (N=253), 18-75yrs with sTBI, were assessed for genetic relationships with PTS. SNPs within SLC1A1 and SLC1A6 were assayed. Kaplan-Meier estimates and log-rank statistics were used to compare seizure rates from injury to 3yrs post-injury for SNPs by genotype. Hazard ratios were estimated using Cox proportional hazards regression for SNPs significant in Kaplan-Meier analyses adjusting for known PTS risk factors. Results 32 tagging SNPs were examined (SLC1A1: n=28, SLC1A6: n=4). 49 (19.37%) subjects had PTS. Of these, 18 (36.7%) seized within 7days, and 31 (63.3%) seized between 8d-3yrs post-TBI. Correcting for multiple comparisons, genotypes at SNP rs10974620 (SLC1A1) were significantly associated with time-to-first seizure across the full 3yr follow-up (seizure rates: 77.1% minor allele homozygotes, 24.8% heterozygotes, 16.6% major allele homozygotes; p=0.001). When follow-up began day 2, genotypes at SNP rs7858819 (SLC1A1) were significantly associated with PTS risk (seizure rates: 52.7% minor allele homozygotes, 11.8% heterozygotes, 21.1% major allele homozygotes; p=0.002). Adjusting for covariates, rs10974620 remained significant (p=0.017, minor allele versus major allele homozygotes HR: 3.4, 95%CI: 1.3-9.3). rs7858819 also remained significant in adjusted models (p=0.023, minor allele versus major allele homozygotes HR: 3.4, 95%CI: 1.1-10.5). Significance Variations within SLC1A1 are associated with risk of epileptogenesis following sTBI. Future studies need to confirm findings, but variation within neuronal glutamate transporter genes may represent a possible pharmaceutical target for PTS prevention and treatment.

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Variation in SLC1A1 is related to combat-related posttraumatic stress disorder

Cited by 9 publications

References 39 publications

Reduced Slc1a1 expression is associated with neuroinflammation and impaired sensorimotor gating and cognitive performance in mice: Implications for schizophrenia

Reduced Slc1a1 expression is associated with neuroinflammation and impaired sensorimotor gating and cognitive performance in mice: Implications for schizophrenia

Glutamate dysregulation and glutamatergic therapeutics for PTSD: Evidence from human studies

Genetic variation in neuronal glutamate transport genes and associations with posttraumatic seizure

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