Chronic Neonatal Tiagabine Treatment Attenuates Hippocampal Abnormalities in the Ts65Dn Mouse Model of Down Syndrome

ABSTRACT

Down syndrome (DS) is a genetic aneuploidy characterized by a variable phenotype that includes a certain degree of intellectual disability. These alterations have been associated with impaired cell proliferation, reduced structural plasticity, and imbalances in inhibitory‐excitatory neurotransmission. Adults with DS exhibit increased inhibition, whereas fetuses and newborns display deficits in inhibitory signaling. In this study, we confirmed that new‐born Ts65Dn mice, the most widely used model of DS, show a reduction in inhibitory synapses. We treated Ts65Dn pups daily for 4 weeks after birth with tiagabine, a GABA transporter 1 inhibitor that increases extracellular GABA levels, in an attempt to restore normal inhibition. This early intervention restored the total number of synapses and normalized the excess of inhibitory contacts previously described in the adult Ts65Dn hippocampus. The expression of plasticity‐related molecules, such as PSA‐NCAM, increased in parallel with the recovery of spine density on granule cells and thorny excrescences on CA3 pyramidal neurons. Moreover, cell proliferation, neurogenesis, and cellular activity were restored to control levels. Overall, these results indicate that early intervention targeting GABAergic neurotransmission during a critical developmental window may be an effective strategy to reverse hippocampal alterations in Ts65Dn mice and suggest that GAT‐1 may have therapeutic potential for individuals with DS.

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