Reverse Translation of Psychosis - associated Hippocampal Hyperactivity in the mouse

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ABSTRACT The hippocampus has been implicated in numerous functions related to normal memory and its dysfunction in several diseases. Our lab has investigated the hippocampus in relation to schizophrenia (SZ) pathophysiology using cognitive and behavioral outcomes(1-3) and brain image analyses(4-6). These consistently show that hippocampal (Hipp) activity is elevated in schizophrenic psychosis (SZ), especially in early illness. To test the molecular basis of this hyperactivity, we examined human postmortem hippocampal tissue by subfield, contrasting healthy and schizophrenia cases, using excitatory and inhibitory synaptic markers and Golgi. We found a reduction in GluN1 limited to dentate gyrus (DG) and an increase in markers of synaptic strength in CA3 in the SZ tissue; these changes are consistent with the observations that Lee et al(7) reported in hippocampal cell cultures (see A.1). Lee showed that CA3 pyramidal cell sensitivity is inversely and powerfully controlled by afferent input from DG, with decreased afferent input associated with increased pyramidal cell activity. We have been able to recapitulate this human-specific SZ pathology in a mouse using a DG-selective GluN1 knock out (KO)(8). This back-translation mouse KO demonstrated Hipp hyperactivity and alterations in Hipp-mediated behaviors (8). We are piloting an inhibitory DREADD technique in DG to mimic the DG-selective GluN1 KO mouse and saw evidence of a sensitive period during ‘adolescence’, when reduced DG activity could stimulate hyperactivity in CA3/CA1. This time phase cannot be resolved in the KO animal, so we had not seen it before and can only study it using DREADDs. The goal of these experiments are to causally define the mechanisms underlying the neurobiological outcomes of temporary DG hypofunction in mouse using DREADD constructs, and to show the extent, development, and critical periods of vulnerability of brain-wide changes. Having found a discrete circuit of Hipp projection regions hyperactive in the KO mouse, we will test human SZ vs HC tissue in these regions for evidence of hyperactivity and coherence with Hipp. The goal is to build a model of how hippocampal hyperactivity affects behavior and brain pathology, and specifically how this tissue pathology could support aberrant memories with psychotic content.