Impaired Hippocampal Circuitry and Memory Dysfunction in Schizophrenia

Pattern separation and pattern completion are opposing yet complementary components of mnemonic processing that heavily rely on the hippocampus. It has been shown that processing within the dentate gyrus (DG) subfield promotes pattern separation while operations within the CA3 subfield are important for pattern completion. Schizophrenia has been associated with anatomical and functional hippocampal abnormalities, including within the DG and CA3. We hypothesized that an impairment in hippocampal circuitry in individuals with first-episode schizophrenia leads to deficits in pattern separation (mnemonic discrimination) and pattern completion (recognition memory), that these deficits contribute to delusions, and that antipsychotic treatment improves circuit functioning. We measured behavioral and neural responses during the identification of new, repeated, and similar stimuli using high-resolution fMRI in 45 medication-free or minimally-treated individuals with first-episode schizophrenia (FES) and 49 matched healthy controls (HC). We found recognition memory and pattern separation deficits in FES and a negative association between memory performance and the severity of delusions. Neural analyses revealed deficits in BOLD responses in the hippocampus during mnemonic discrimination in FES compared to HC. Importantly, by investigating the association between trial-level neural activity and behavior before and after treatment, we found that antipsychotics normalized DG activity during pattern separation. Lastly, trial-level cortical responses during mnemonic discrimination predicted performance in FES at baseline, suggesting a compensatory role. This case-control study provides important insight into the impact of schizophrenia and antipsychotic treatment on memory systems and uncovers systems-level contributions to pattern separation and pattern completion.