NPTX2 transfection improves synaptic E/I balance and performance in learning impaired aged rats

Excessive neural activity in the medial temporal lobe commonly associates with cognitive decline in elderly humans and also in rodents.An attractive model pathway to study synaptic mechanisms underlying age-dependent circuit hyperexcitability is the connection made by lateral entorhinal cortex cells onto the dentate gyrus (LEC→DG). Both structures are particularly affected by age and, importantly, in behaviorally characterized aged rats, learning impairment correlates with diminished feedforward inhibition of granule cells recruited by LEC inputs. In this rat model of aging, we evaluated how overexpression of Neuronal Pentraxin 2 (NPTX2) in the LEC, essential for stabilizing excitatory inputs onto fast-spiking inhibitory interneurons (FS-INs), enhances feedforward inhibition and improves spatial memory in impaired individuals. In addition, we found that FS-INs from unimpaired aged individuals have an increased excitatory drive compared to young individuals. These findings support the notion that NPTX2-mediated compensatory mechanisms to enhance the recruitment of FS-INs are crucial to maintaining proficient memory performance during aging.