PROJECT SUMMARY Alzheimer’s disease is characterized by pathological protein aggregates comprised of β-amyloid plaques and tau neurofibrillary tangles. Mainstream hypotheses highlight synaptic dysfunction and eventual neuronal atrophy as culprits for symptoms such as mood disorders, cognitive function, and impaired spatial learning and memory. The shortage of effective treatments highlights the gap in etiologic understanding of AD progression. While deficits in glutamatergic neurotransmission and atrophy of cholinergic forebrain neurons have been extensively studied, GABAergic transmission remains poorly understood in the context of AD. A key subpopulation of GABAergic neurons in the medial septum (MS-GABA) project exclusively to the hippocampus where they contact local inhibitory interneurons to support theta rhythm, spatial learning and memory, and adult neurogenesis. MS-GABA circuit dysfunction and degeneration is commonly observed in mouse models but has not yet been investigated in the 3xtg-AD line, thought to closely mimic AD progression. Circuit manipulation studies are emergent therapeutic strategies in neurological disorders. Therefore, we propose the use of chemogenetics to modulate the activity of the MS-GABA circuit in AD. We expect early MS-GABA stimulation to rebalance glutamate and GABA within the hippocampus of 3xtg-AD mice and expect recovery in spatial learning and memory deficits. These studies will facilitate identification of critical periods in prodromal stages of AD and test a novel therapeutic intervention strategy during these stages.