Behavioral and synaptic alterations relevant to obsessive-compulsive disorder in mice with increased EAAT3 expression
| Autor: | Elias Utreras, Andrés E. Chávez, Anna K. Radke, Andrew Cho, Angélica P. Escobar, Ayesha Sengupta, Ashok B. Kulkarni, Sebastián F. Estay, Jens R. Wendland, Dennis L. Murphy, Pablo R. Moya, Andrew Holmes, Francisca Henríquez-Belmar, Ramón Sotomayor-Zárate, Valentina Haro-Acuña, Claudia Delgado-Acevedo, Cristopher A. Reyes |
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| Rok vydání: | 2018 |
| Předmět: |
Genetically modified mouse
Clomipramine Candidate gene Obsessive-Compulsive Disorder Patch-Clamp Techniques Gene Expression Mice Transgenic Biology Anxiety Cell Line 03 medical and health sciences Glutamatergic Mice Neuroblastoma 0302 clinical medicine Fluoxetine medicine Animals Pharmacology Cerebral Cortex Neuronal Plasticity Behavior Animal SLC1A1 Correction 030227 psychiatry Neostriatum Psychiatry and Mental health Disease Models Animal Excitatory Amino Acid Transporter 3 Synaptic plasticity biology.protein NMDA receptor Calcium-Calmodulin-Dependent Protein Kinase Type 2 Neuroscience 030217 neurology & neurosurgery Selective Serotonin Reuptake Inhibitors medicine.drug |
| Zdroj: | Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 44(6) |
| ISSN: | 1740-634X |
| Popis: | 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 (EAAT3glo) 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 (EAAT3glo/CMKII) displayed increased anxiety-like and repetitive behaviors that were both restored by chronic, but not acute, treatment with fluoxetine or clomipramine. EAAT3glo/CMKII mice also displayed greater spontaneous recovery of conditioned fear. Electrophysiological and biochemical analyses at corticostriatal synapses of EAAT3glo/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. |
| Databáze: | OpenAIRE |
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