To characterize cell-type-specific impairments in the lateral entorhinal cortex (LEC)-hippocampal CA1 system in Alzheimer’s Disease (AD) and pharmacologically rescue associated synaptic physiology deficits via cholinergic neuromodulation of VIP+ interneurons in the LEC-CA1 circuit.

Preclinical AD stage indicates early dysfunction in LEC, leading to progressive spread of disease pathology into downstream hippocampal areas. Quantifying cell-type-specific vulnerabilities in this LEC-CA1 pathway is crucial to inform cellular mechanisms underlying the hallmark synaptic deficits in early AD. Our recent functional mapping identified that LEC bidirectionally gates CA1 pyramidal neuron activity and subsequent E/I balance by projecting glutamatergic inputs to inhibitory Cholecystokinin (CCK) interneurons (INs) and disinhibitory Vasoactive Intestinal Peptide (VIP) INs which target CCK and somatostatin-INs. Neuromodulation of nicotinic acetylcholine (α4β2) receptors on VIP+ INs provides a selective target for translatable early-stage therapeutics.

Using APP NL-G-F Knock-In (APP KI) mice and age-matched WT mice (6-8 mo, >12 mo), we quantified changes in the fluorescent density of LEC glutamatergic cell bodies and their projections to hippocampal CA1, CA3, and dentate gyrus (DG). Next, we treat the mice with chronic nicotine IP injections for 7 days to stimulate α4β2R+ in VIP INs and activate their downstream disinhibition of PN activity in CA1 to rescue E/I balance. We then perform pathway-specific stimulation of EC vs CA3 inputs and extracellular field recordings in CA1 of acute hippocampal slices to assess synaptic transmission and measure changes in their input-output and LTP.

Preliminary data suggest a degradation in LEC glutamatergic projection and progressively diminishing LEC-CA1 drive by 12 months in APP-KI mice. Acute slice field recordings indicate that decreased CA3-CA1 Schaffer Collateral SR and EC-CA1 SLM stimulation-evoked fPSPs in AD mice are rescued up to WT levels upon chronic nicotine treatment.