Pharmacological reduction of reverse-translated hippocampal hyperactivity in mouse: relevance for psychosis

Hippocampal hyperactivity (HH) is a potential biomarker in schizophrenia psychosis, which also appears in several other brain disorders, compromising specificity. We hypothesized that the reversal of HH in an established, reverse-translational animal preparation, coupled with a behavioral marker of psychosis may be a predictor of antipsychotic efficacy of a medication. We used a chemogenetic reverse-translational mouse preparation relevant to schizophrenia psychosis which shows HH and aberrant psychosis-relevant behaviors, specifically disrupted social recognition memory (SRM). Mice with and without HH were treated with three drugs; two known antipsychotics and one HH-reducing anticonvulsant, to assess their effects on both HH and SRM performance. All animals received one of the four treatments: vehicle (N = 15-24), haloperidol (N = 8-15), xanomeline (N = 8-13) or levetiracetam (N = 6-15) and were subsequently tested for baseline c-Fos protein expression within the hippocampal subfields (CA3 and CA1) as a measure of neuronal activity, or tested with the SRM task as a measure of social memory. All three drugs acutely reduced baseline HH compared to vehicle treatment. Subacute administration of haloperidol or xanomeline, the two drugs known to have antipsychotic activity, but not levetiracetam, normalized the SRM behavior to control levels. These results suggest that the reversal of HH alone cannot be a predictor of antipsychotic efficacy of an experimental drug and HH as a biomarker could benefit from a more sensitive readout approach.