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.