Contributions of hippocampal oxytocin receptors to social recognition

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Project Summary Prior to neuronal loss in the medial temporal lobe in Alzheimer's disease (AD), there are numerous pathological changes including alterations in ABeta and tau, inflammation and microglial functions and neural circuit/synaptic dysfunction that are associated with a mild cognitive impairment (MCI). fMRI studies have documented hippocampal hyperactivity and alterations in dentate gyrus (DG)-CA3 dependent functions such as pattern separation-pattern completion balance in MCI and during aging. Behaviorally, this manifests as episodic (including social) memory imprecision. At a circuit level, excitation-inhibition (E-I) imbalance in DG-CA3 are associated with these cognitive changes. Furthermore, the antiepileptic drug levetiracetam has been shown to decrease DG-CA3 hyperactivity and improve cognition in individuals with MCI and ameliorate E-I imbalance in AD mouse models. Importantly, direct optogenetic stimulation of parvalbumin basket cells or chemogenetic attenuation of neural activity decreases amyloid load in multiple mouse models of AD. These observations from human and mouse studies suggest that decreasing neuronal hyperactivity and recruiting GABAergic inhibition may directly modulate amyloid plaque burden and memory impairment. Here, we will build on our preliminary data and will investigate how a molecular factor that promotes recruitment of PV INs, Ablim3, maybe harnessed to increase feed-forward inhibition in DG-CA3 circuit of the APPNL-F knock-in mouse model of AD, decrease amyloid load, reduce CA1 hyperactivity, and improve social memory precision. Together, the proposed Aims will leverage ongoing efforts investigating how oxytocin receptors in DG-CA3 circuitry modulate social memory precision in the parent NIMH Ro1 while conveying a new direction that may illuminate the therapeutic potential of harnessing Ablim3 to dampen hippocampal DG-CA3 hyperactivity, reduce amyloid burden and improve social memory precision in AD.