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

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 tiss...

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Published in:Neuropsychopharmacology (New York, N.Y.) N.Y.), 2019-05, Vol.44 (6), p.1163-1173
Main Authors: Delgado-Acevedo, Claudia, Estay, Sebastián F, Radke, Anna K, Sengupta, Ayesha, Escobar, Angélica P, Henríquez-Belmar, Francisca, Reyes, Cristopher A, Haro-Acuña, Valentina, Utreras, Elías, Sotomayor-Zárate, Ramón, Cho, Andrew, Wendland, Jens R, Kulkarni, Ashok B, Holmes, Andrew, Murphy, Dennis L, Chávez, Andrés E, Moya, Pablo R
Format: Article
Language:English
Subjects:
Animal models
Animals
Anxiety
Anxiety - metabolism
Behavior
Behavior, Animal - physiology
Behavioral plasticity
Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism
Cell Line
Cerebral Cortex - metabolism
Clomipramine
Clomipramine - pharmacology
Conditioning
Cortex
Disease Models, Animal
Excitatory Amino Acid Transporter 3 - genetics
Excitatory Amino Acid Transporter 3 - metabolism
Fear conditioning
Fluoxetine
Fluoxetine - pharmacology
Gene Expression - genetics
Glutamatergic transmission
Glutamic acid receptors (ionotropic)
Glutamic acid transporter
Mental disorders
Mice
Mice, Transgenic
N-Methyl-D-aspartic acid receptors
Neostriatum - metabolism
Neuroblastoma
Neuronal Plasticity - physiology
Neuroses
Obsessive compulsive disorder
Obsessive-Compulsive Disorder - metabolism
Patch-Clamp Techniques
Serotonin Uptake Inhibitors - pharmacology
Spontaneous recovery
Subunit structure
Synapses
Synaptic plasticity
Transgenic mice
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Summary: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 ) 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 /CMKII) displayed increased anxiety-like and repetitive behaviors that were both restored by chronic, but not acute, treatment with fluoxetine or clomipramine. EAAT3 /CMKII mice also displayed greater spontaneous recovery of conditioned fear. Electrophysiological and biochemical analyses at corticostriatal synapses of EAAT3 /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.
ISSN:0893-133X
1740-634X
1740-634X
DOI:10.1038/s41386-018-0302-7