The dynamic impairment of synaptic transmission in the PCx-IL engram circuit contributes to early olfactory memory decline in Alzheimer's disease

Olfactory dysfunction has emerged as a promising target for early diagnosis and treatment of Alzheimer's disease (AD). However, the mechanisms underlying the neural circuit disruptions associated with olfactory dysfunction in AD remain poorly understood. In this study, clinical fMRI image data revealed that connectivity between piriform cortex (PCx) and infralimbic cortex (IL) was impaired during the early mild cognitive impairment (MCI) stage of AD, which associated with abnormalities in the 5-HT, GABAergic and Glutamate neurotransmitters. Optogenetic stimulation of IL-projecting PCx engram neurons successfully improved olfactory memory retrieval deficits in 5xFAD mice. In addition, single-cell RNA sequencing was employed to investigate the damage mechanisms in IL engram cells, which revealed increased glutamate expression and impaired synaptic function as key changes. Guided by the single-cell sequencing data, we analyzed glutamatergic synaptic transmission in the PCx-IL engram cell circuit in 5xFAD mice. The results indicated dynamic impairments in GluA2 receptor-associated synaptic transmission within this circuit. Importantly, optical long-term potentiation (LTP) of synaptic transmission restored directional engram synaptic transmission and prevented olfactory memory decline. These results suggest that dynamic impairment of synaptic transmission in the PCx-IL engram cell circuit underlies the early decline in olfactory memory in AD. Therefore, PCx-IL functional connnetion impairment may be a new target for diagnosis and therapy to the early stage of AD.