Hippocampal Long-Term Potentiation Suppressed by Increased Inhibition in the Ts65Dn Mouse, a Genetic Model of Down Syndrome

TLDR

Down syndrome, caused by trisomy 21, leads to learning and memory impairments linked to hippocampal dysfunction, yet the neurobiological mechanisms underlying these deficits remain poorly understood. The study aimed to investigate the cellular basis of hippocampal dysfunction in Ts65Dn mice, a genetic model of Down syndrome. Researchers examined synaptic transmission and long‑term potentiation in the dentate gyrus of Ts65Dn mice, finding normal basal transmission but severely impaired LTP due to reduced NMDA receptor activation, and demonstrated that blocking GABA_A‑mediated inhibition with picrotoxin restored NMDA currents and LTP. The results indicate that enhanced inhibition, likely from presynaptic abnormalities, suppresses NMDA receptor activity and LTP in Ts65Dn mice, suggesting that similar mechanisms may underlie learning deficits in Down syndrome and other developmental disorders.

Abstract

Although many genetic disorders are characterized by cognitive failure during development, there is little insight into the neurobiological basis for the abnormalities. Down syndrome (DS), a disorder caused by the presence of three copies of chromosome 21 (trisomy 21), is characterized by impairments in learning and memory attributable to dysfunction of the hippocampus. We explored the cellular basis for these abnormalities in Ts65Dn mice, a genetic model for DS. Although basal synaptic transmission in the dentate gyrus was normal, there was severe impairment of long-term potentiation (LTP) as a result of reduced activation of NMDA receptors. After suppressing inhibition with picrotoxin, a GABA A receptor antagonist, NMDA receptor-mediated currents were normalized and induction of LTP was restored. Several lines of evidence suggest that inhibition in the Ts65Dn dentate gyrus was enhanced, at least in part, because of presynaptic abnormalities. These findings raise the possibility that similar changes contribute to abnormalities in learning and memory in people with DS and, perhaps, in other developmental disorders with cognitive failure.