GABAergic Circuit Targets for Modulating Entorhinal Cortex and Hippocampal Dynamics in Alzheimer's Disease

Alzheimer’s disease (AD) patients, even in the mild cognitive impairment stage, show pronounced memory impairment that correlates with AD pathology in the entorhinal cortex (EC) - hippocampus circuit. Within the EC-hippocampal network, the lateral EC (LEC) and hippocampal area CA1 are most susceptible. Yet, there is a gap in our knowledge of potential cellular targets and pathway-specific neuromodulatory mechanisms for devising effective and translatable early- stage therapeutic strategies in humans. Our study aims to fill this gap by examining the GABAergic microcircuits within CA1, specifically those driven by vasoactive intestinal peptide (VIP+) and cholecystokinin (CCK+) inhibitory neurons (INs) that gate activity from LEC, with a hypothesis that modulating activity in these two circuits can improve LEC-CA1 dynamics and related memory-guided behavior. This hypothesis is bolstered by exciting preliminary data establishing a framework that delineates strong excitation of CA1 pyramidal neurons (PN) dendrites by LEC that is modulated by opposing impacts disinhibition by VIP+ INs and inhibition by CCK+ INs, which in turn may be tuned by cholinergic and cannabinoid modulation, respectively. In this ground-breaking collaboration between a neuroscientist (Basu) specializing in cortico-hippocampal circuit function and a physician-scientist (Masurkar) with expertise in early Alzheimer’s disease- related circuit dysfunction, we will perform a cross-species comparison of GABAergic circuits in area CA1 of AD mouse models and human patients to assess their pathological resilience and vulnerability across disease stages. To achieve our goal of developing translatable and effective targeted therapeutics, we will use a multifaceted approach leveraging our (i) recently acquired in-depth knowhow of LEC-CA1 circuitry, (ii) experience in assessing neural circuit dynamics using slice electrophysiology and in vivo two-photon imaging during behavior, and (iii) expertise in proteomic analysis in post- mortem human patient tissue. Our pilot experiments show that aged AD model mice show smaller LEC-evoked responses and cortico-hippocampal plasticity. In vivo 2P imaging in younger APP-KI shows place cell remapping deficits, and lag in spatial context-dependent memory behavior. Using this groundwork, our study will link AD-related changes in LEC-CA1 excitatory-inhibitory-disinhibitory circuit dynamics with deficits in plasticity, place coding, and associational memory behavior in the recently developed APP-KI AD and more established 5xFAD mouse models. In Aim 1, we will use in vitro opto-electrophysiology in the 2 AD models to evaluate altered LEC-driven excitatory-inhibitory dynamics in CA1 PNs and their rescue efficacy using cholinergic and cannabinoid neuromodulation of VIP+ IN and CCK+ IN activity. In Aim 2, we will apply in vivo 2P microscopy in awake-behaving mice to test that context and odor-cued spatial memory behavior and place cell activity are impaired in AD mice and can be rescued by retuning CA1 activity through chronic neuromodulation of VIP + and CCK+ INs. In Aim 3, we use immunohistology and localized proteomics in human post- mortem brain tissue to test that CA1 VIP+ and CCK+ INs have integrity relative to PNs to be engaged in early human AD. Together, our study will reveal specific neuron types and modulatory mechanisms that warrant future investigation as circuit targets and strategies for more effective early-stage AD therapeutics. Project Number: 1R01AG094086-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Jayeeta Basu (+1 co-PI) | Institution: NEW YORK UNIVERSITY SCHOOL OF MEDICINE, NEW YORK, NY | Award Amount: $642,063 | Activity Code: R01 | Study Section: Learning, Memory and Decision Neuroscience Study Section[LMDN] View on NIH RePORTER: https://reporter.nih.gov/project-details/11301449