Deciphering Dentate Gyrus Malfunction in Age-Dependent Hippocampal Hyperactivity: Implications for Psychogenesis - PROJECT SUMMARY The dentate gyrus (DG), a part of the hippocampus (HPC), plays a pivotal role in encoding and retrieving episodic memory. A mounting body of research implicates HPC abnormalities, including those in the DG, in the pathophysiology of psychosis. This includes observed structural and functional changes in the HPC of individuals suffering from psychosis, such as those diagnosed with schizophrenia (ScZ). Pertinently, studies have identified decreased neurogenesis and changes in the morphology and functionality of DG granule cells in both animal models of psychosis and postmortem brain analyses of ScZ patients. ScZ is a complex mental disorder marked by a mix of symptoms: hallucinations, delusions, disorganized thinking, and impaired social functioning. The onset of ScZ varies, but there's a known age dependence with symptoms typically appearing from late adolescence to early adulthood, generally between the late teens and early thirties. Emerging evidence proposes a potential correlation between age-dependent dysfunction in the dentate gyrus (DG) and psychosis, although the exact nature of this relationship remains unclear. In this proposal, our objective is to reverse-translate discoveries from post-mortem human brain analyses. We specifically target DG excitatory neurons, aiming to modulate them using the chemogenetic technique known as DREADD (Designer Receptors Exclusively Activated by Designer Drugs) to gradually inhibit DG activity in the HPC in an age-dependent fashion. Concurrently, we will longitudinally monitor HPC activity using a chronic high- density in vivo recording strategy. Our hypothesis is that a reduction in DG activity in the HPC will instigate abnormal hyper-excitable neuronal activity in downstream CA3 / CA1 regions during adolescence, propagating into the entorhinal cortex (EC), which will subsequently disrupt normal brain activities, including oscillatory patterns and neuronal spiking activities, post adolescence. Preliminary data show the emergence of large, spontaneous, irregular hypersynchronous activity in the HPC, which evolves over time and persists into adulthood in mice. This spontaneous activity is characterized by large transient local-field potential (LFP) deflections coupled with large population spiking activity that has a temporal structure lasting for 50-100 milliseconds. Notably, these hyper-synchronous events tend to occur during quiet wake or slow-wave sleep periods, but not during active running states. Our aim is to consolidate two working hypotheses in this grant period: (i) how gradual suppression of DG triggers the hyper-synchronous events in HPC; (ii) the how the hyper-synchronous events impact normal sharp-wave ripples (SWRs) and behavior. We anticipate that our modeling and investigation of the early onset of ScZ, extrapolated from post-mortem brain analyses of human patients, will illuminate the neurological processes occurring in the adolescent brain during quiet / sleep periods, and aim to eventually submit a full five-year research proposal.
