The medial septum-hippocampus-lateral septum circuitry in spatial memory: linking healthy function to early Alzheimer’s disease and translational opportunities

Hippocampus (HPC)-associated spatial memory deficits are one of the earliest symptoms of Alzheimer’s disease (AD). Current pharmacological treatments only alleviate the symptoms but do not prevent disease progression. The emergence of neuromodulation technology suggests that specific neural circuits are potential therapeutic targets for AD. Current studies have analyzed the medial septum (MS)–HPC and the HPC–lateral septum (LS) circuitries separately. A comprehensive understanding of their synergistic effects and overall dysregulation in AD remains limited. In this review, we will integrate anatomical and functional evidence to give an overview of the role of the MS–HPC–LS circuitry in spatial memory, the mechanisms of AD-related dysregulation, and therapeutic strategies targeting the circuitry, specially focusing on molecular interventions (receptor modulation) and bioengineering strategies (circuit-specific stimulation).