Basic Science and Pathogenesis

Familial Danish Dementia (FDD) patients carry a heterozygous Itm2b mutation, which has been modeled in the FDD knock-in (KI) rat to investigate synaptic alterations over time. Previous studies have shown increased basal synaptic transmission (BST) in young adult FDD-KI rats; however, there is limited information regarding long-term potentiation (LTP) changes with age and how the presence of the App δ58 allele influences synaptic function.

To evaluate age-related synaptic changes, we performed BST and LTP recordings in hippocampal slices from 7-month-old FDD-KI/App^h/h rats of both sexes. Additionally, we examined the effects of the App δ58 allele by crossing FDD-KI rats with App^δ58/h rats and conducting electrophysiological recordings.

BST was significantly increased in 7-month-old FDD-KI/App^h/h rats compared to controls, consistent with findings in younger rats. However, the fiber volley (FV) amplitude was elevated at 7 months, suggesting increased afferent activation, which was not observed in younger rats. LTP was significantly impaired in 7-month-old FDD-KI/App^h/h rats, with reductions in both early (E-LTP) and late phases (L-LTP), while short-term potentiation (STP) remained unaffected. In FDD-KI/App^δ58/h rats, BST and FV amplitude were similarly increased, but LTP impairments persisted, indicating that the App δ58 allele does not rescue synaptic deficits.

Our findings demonstrate that synaptic excitability increases with age in FDD-KI rats, accompanied by progressive LTP impairments. The presence of the App δ58 allele does not mitigate LTP deficits, highlighting the persistent impact of the Itm2b mutation on hippocampal function in the FDD model. These findings provide new insights into the synaptic changes associated with aging in FDD, addressing the previously unexplored LTP alterations.