Optogenetic modulation of spatial hippocampal representations in a mouse model of Alzheimer’s disease

Disrupted neural oscillations and memory are common features of Alzheimer's disease (AD). Our previous studies have demonstrated the potential to restore theta oscillations by utilizing LFP-guided closed-loop optogenetic stimulation of local parvalbumin-positive (PV+) interneurons in the CA1 region of the hippocampus in APP/PS1dE9 mice. Furthermore, employing the same protocol, we successfully enhanced the performance of transgenic mice in a spatial memory tests. Based on these findings, our objective is to investigate the impact of PV+ stimulation on circuit function within the CA1 region. To achieve this, we utilize the APP/PS1dE9 mouse model with an Aβ-pathology, specifically expressing an excitatory opsin in local PV+ interneurons and a functional Ca2+-reporter in CA1 pyramidal neurons. We subject head-fixed mice to a spatial reward-learning and memory task on a linear treadmill, while simultaneously evaluating neuronal population coding. In this context, our goal is to identify behavioral disparities, as well as neuronal network deficits relevant for cognition in APP/PS1dE9 mice. We will determine, if temporally and spatially controlled PV+ interneuron-mediated synchronization of CA1 population activity affects spatial representation. We will investigate, whether PV+ modulation ultimately can be employed to ameliorate the identified deficits. These results might be important for the development of future gene-therapy based approaches aiming at PV+ neurons in humans.