title: Adult-onset fluoxetine treatment does not improve behavioral impairments and may have adverse effects on the Ts65Dn mouse model of Down syndrome.
abstract: Down syndrome is caused by triplication of chromosome 21 and is associated with neurocognitive phenotypes ranging from severe intellectual disability to various patterns of more selective neuropsychological deficits, including memory impairments. In the Ts65Dn mouse model of Down syndrome, excessive GABAergic neurotransmission results in local over-inhibition of hippocampal circuits, which dampens hippocampal synaptic plasticity and contributes to cognitive impairments. Treatments with several GABA(A) receptor antagonists result in increased plasticity and improved memory deficits in Ts65Dn mice. These GABA(A) receptor antagonists are, however, not suitable for clinical applications. The selective serotonin reuptake inhibitor fluoxetine, in contrast, is a widely prescribed antidepressant that can also enhance plasticity in the adult rodent brain by lowering GABAergic inhibition. For these reasons, we wondered if an adult-onset 4-week oral fluoxetine treatment restores spatial learning and memory impairments in Ts65Dn mice. Fluoxetine did not measurably improve behavioral impairments of Ts65Dn mice. On the contrary, we observed seizures and mortality in fluoxetine-treated Ts65Dn mice, raising the possibility of a drug × genotype interaction with respect to these adverse treatment outcomes. Future studies should re-address this in larger animal cohorts and determine if fluoxetine treatment is associated with adverse treatment effects in individuals with Down syndrome.
authors: DZNE, German Center for Neurodegenerative Diseases, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
authors: Markus
authors: M
authors: Heinen
authors: Moritz M
authors: MM
authors: Hettich
authors: Devon P
authors: DP
authors: Ryan
authors: Susanne
authors: S
authors: Schnell
authors: Katharina
authors: K
authors: Paesler
authors: Dan
authors: D
authors: Ehninger
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D002452:Cell Count; D003072:Cognition Disorders / Q000188:drug therapy / Q000523:psychology; D004314:Down Syndrome / Q000188:drug therapy* / Q000235:genetics / Q000523:psychology*; D005260:Female; D005473:Fluoxetine / Q000009:adverse effects / Q000494:pharmacology*; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D005838:Genotype; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000188:drug therapy / Q000209:etiology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced / Q000401:mortality; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects / Q000494:pharmacology*
chemical_list: D005473:Fluoxetine; D058787:GABA-A Receptor Antagonists; D017367:Selective Serotonin Reuptake Inhibitors