Abstract
Adaptable and consistent neural function relies at least in part on the ongoing repair of oxidative damage that can accumulate in the brain over a lifespan. To determine whether forebrain neuron-targeted knockout of AP endonuclease 1 (APE1), a critical enzyme in the base excision DNA repair pathway, contributes to neuronal impairments, we generated APE1 conditional knockout mice under the control of the CamKIIα promotor (APE1 cKO). Spatial learning and memory were tested using the Morris water maze. Synaptic markers, including synapsin, vGLUT, GABA1, and GAD were immunostained and quantified. Dendritic morphology and number were characterized using Golgi staining. Long-term potentiation (LTP) was measured in slices from the 6-month-old brain. APE1 cKO mice did not significantly differ from WT mice in the learning phase of the Morris water maze, but performed significantly worse during the memory phase of the Morris water maze. vGLUT, GABA1, and GAD immunostaining was significantly decreased in APE1 cKO mice without concomitant changes in the number of synapsin-positive structures, suggesting that neural networks may be impaired but not at the level of total presynaptic structures. Dendrites were reduced both in number and length of spines in APE1 cKO mice. APE1 cKO brain slices exhibited decreased LTP induction compared to WT brain slices. Together, these data indicate that the conditional loss of APE1 in forebrain neurons leads to a phenotype consistent with expedited brain aging.