Neurochemical and behavioral characterization of neuronal glutamate transporter EAAT3 heterozygous mice

González, Luis; Henríquez-Belmar, Francisca; Delgado-Acevedo, Claudia; Cisternas-Olmedo, Marisol; Arriagada, Gloria; Sotomayor‐Zárate, Ramón; Murphy, Dennis L.; Moya, Pablo R.

doi:10.1186/s40659-017-0138-3

Cited by 10 publications

(8 citation statements)

References 37 publications

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“…Our results are in agreement with this hypothesis, by showing that EAAT3 glo /CMKII mice display increased behaviors that are relevant to OCD. Of note, several reports using different mouse models fully or partially lacking EAAT3 have shown unaltered baseline anxiety-like or repetitive behaviors, indirectly supporting the potential involvement of EAAT3 gain-of-function in behaviors relevant to OCD [39,40,60] (however, see [61]).…”

Section: Discussionmentioning

confidence: 94%

“…Several animal models fully or partially lacking EAAT3 have shown no alterations in baseline behaviors relevant to OCD [39,40,41]. Interestingly, the rs301430C allele, a SLC1A1 polymorphism highly replicated in OCD studies is associated with increased transcript levels in human brain tissue [27], suggesting that overexpression could contribute to OCD susceptibility [4].…”

Section: Introductionmentioning

confidence: 99%

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Behavioral and synaptic alterations relevant to obsessive-compulsive disorder in mice with increased EAAT3 expression

Delgado-Acevedo

Estay

Radke

et al. 2018

Neuropsychopharmacol.

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Obsessive-compulsive disorder (OCD) is a severe, chronic neuropsychiatric disorder with a strong genetic component. The SLC1A1 gene encoding the neuronal glutamate transporter EAAT3 has been proposed as a candidate gene for this disorder. Gene variants affecting SLC1A1 expression in human brain tissue have been associated with OCD. Several mouse models fully or partially lacking EAAT3 have shown no alterations in baseline anxiety-like or repetitive behaviors. We generated a transgenic mouse model (EAAT3 glo) to achieve conditional, Cre-dependent EAAT3 overexpression and evaluated the overall impact of increased EAAT3 expression at behavioral and synaptic levels. Mice with EAAT3 overexpression driven by CaMKIIα-promoter (EAAT3 glo /CMKII) displayed increased anxiety-like and repetitive behaviors that were both restored by chronic, but not acute, treatment with fluoxetine or clomipramine. EAAT3 glo /CMKII mice also displayed greater spontaneous recovery of conditioned fear. Electrophysiological and biochemical analyses at corticostriatal synapses of EAAT3 glo /CMKII mice revealed changes in NMDA receptor subunit composition and altered NMDA-dependent synaptic plasticity. By recapitulating relevant behavioral, neurophysiological, and psychopharmacological aspects, our results provide support for the glutamatergic hypothesis of OCD, particularly for the increased EAAT3 function, and provide a valuable animal model that may open novel therapeutic approaches to treat this devastating disorder.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Behavioral and synaptic alterations relevant to obsessive-compulsive disorder in mice with increased EAAT3 expression

Delgado-Acevedo

Estay

Radke

et al. 2018

Neuropsychopharmacol.

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“…Of note, behavioral profiling of the Slc1a1 null and STOP mice has primarily focused on comparing homozygous mutant animals with either wildtype littermate controls or age-and sex-matched controls, without extensive characterization of heterozygous animals demonstrating 50% loss of expression. Two groups have recently reported behavioral profiling of animals heterozygous for Slc1a1 and found no change in locomotor activity but reported different results regarding anxiety-like behavior compared to wildtype littermate controls (Afshari et al, 2015;Gonzalez et al, 2017). Heterozygotes also had no response to amphetamine and no change in tissue dopamine levels (Gonzalez et al, 2017).…”

Section: Eaat3 In Development and Adulthoodmentioning

confidence: 99%

“…Two groups have recently reported behavioral profiling of animals heterozygous for Slc1a1 and found no change in locomotor activity but reported different results regarding anxiety-like behavior compared to wildtype littermate controls (Afshari et al, 2015;Gonzalez et al, 2017). Heterozygotes also had no response to amphetamine and no change in tissue dopamine levels (Gonzalez et al, 2017). Overall, the behavioral data across these different studies is not directly comparable because of the use of different mechanisms (null versus STOP versus heterozygote), ages (from weanlings to adults), and controls (littermates versus matched wildtypes).…”

Section: Eaat3 In Development and Adulthoodmentioning

confidence: 99%

Neuronal excitatory amino acid transporter EAAT3: Emerging functions in health and disease

Underhill

Ingram

Ahmari

et al. 2019

Neurochemistry International

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“…Mouse models lacking EAAT3 expression have reported dissimilar results in regard to OCD-like behavior. EAAT3 heterozygous mice were found to have no behavioral or neurochemical alterations relevant to OCD ( González et al, 2017 ). In EAAT3 knockout (KO) mice, early studies found no alterations in anxiety or compulsive-like behaviors at 6–8 weeks old but reported a reduction in self-grooming behavior at 10–12 months old ( Aoyama et al, 2006 ), while a recent study found increased grooming in EAAT3 KO mice at an early age, from postnatal day 14 to 35 ( Bellini et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Altered Grooming Syntax and Amphetamine-Induced Dopamine Release in EAAT3 Overexpressing Mice

Escobar

Martínez-Pinto

Silva-Olivares

et al. 2021

Front. Cell. Neurosci.

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The excitatory amino acid transporter EAAT3 plays an important role in the neuronal uptake of glutamate regulating the activation of glutamate receptors. Polymorphisms in the gene-encoding EAAT3 have been associated with obsessive–compulsive disorder (OCD), although the mechanisms underlying this relationship are still unknown. We recently reported that mice with increased EAAT3 expression in forebrain neurons (EAAT3glo/CMKII) display behavioral and synaptic features relevant to OCD, including increased grooming, higher anxiety-like behavior and altered cortico-striatal synaptic function. The dopamine neurotransmitter system is implicated in ritualistic behaviors. Indeed, dopaminergic neurons express EAAT3, and mice lacking EAAT3 exhibit decreased dopamine release and decreased expression of the dopamine D1 receptor. Moreover, EAAT3 plays a role on the effect of the psychostimulant amphetamine. As such, we sought to determine if the OCD-like behavior in EAAT3glo/CMKII mice is accompanied by altered nigro-striatal dopaminergic transmission. The aim of this study was to analyze dopamine transmission both in basal conditions and after an acute challenge of amphetamine, using behavioral, neurochemical, molecular, and cellular approaches. We found that in basal conditions, EAAT3glo/CMKII mice performed more grooming events and that they remained in phase 1 of the grooming chain syntax compared with control littermates. Administration of amphetamine increased the number of grooming events in control mice, while EAAT3glo/CMKII mice remain unaffected. Interestingly, the grooming syntax of amphetamine-control mice resembled that of EAAT3glo/CMKII mice in basal conditions. Using in vivo microdialysis, we found decreased basal dopamine levels in EAAT3glo/CMKII compared with control mice. Unexpectedly, we found that after acute amphetamine, EAAT3glo/CMKII mice had a higher release of dopamine compared with that of control mice, suggesting that EAAT3 overexpression leads to increased dopamine releasability. To determine postsynaptic effect of EAAT3 overexpression over dopamine transmission, we performed Western blot analysis of dopaminergic proteins and found that EAAT3glo/CMKII mice have higher expression of D2 receptors, suggesting a higher inhibition of the indirect striatal pathway. Together, the data indicate that EAAT3 overexpression impacts on dopamine transmission, making dopamine neurons more sensitive to the effect of amphetamine and leading to a disbalance between the direct and indirect striatal pathways that favors the performance of repetitive behaviors.

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Neurochemical and behavioral characterization of neuronal glutamate transporter EAAT3 heterozygous mice

Cited by 10 publications

References 37 publications

Behavioral and synaptic alterations relevant to obsessive-compulsive disorder in mice with increased EAAT3 expression

Behavioral and synaptic alterations relevant to obsessive-compulsive disorder in mice with increased EAAT3 expression

Neuronal excitatory amino acid transporter EAAT3: Emerging functions in health and disease

Altered Grooming Syntax and Amphetamine-Induced Dopamine Release in EAAT3 Overexpressing Mice

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