S153. IMPAIRED THETA PHASE-COUPLING BETWEEN HIPPOCAMPUS AND MEDIAL PREFRONTAL CORTEX IN SCHIZOPHRENIA

BACKGROUND: A genetic schizophrenia (Scz) mouse model has impaired hippocampal-prefrontal synchrony during spatial working memory (Sigurdsson et al., 2000, Nature). These Df(16)A(+/-) mice (models of the human 22q11.2 microdeletion) have impaired mPFC phase coupling to hippocampal theta (1–8 Hz) oscillations, which predicts performance. This deficit has never been demonstrated in human Scz subjects, however, and its mechanistic basis is unclear. METHODS: 18 Scz (8 unmedicated) and 26 age, gender and IQ-matched controls performed a spatial memory task whilst undergoing magnetoencephalography (MEG), and a ‘memory integration’ task dependent on hippocampal function (without MEG). A partly overlapping group of 33 Scz and 29 controls underwent positron emission tomography (PET) to measure the availability of GABAARs expressing the α5 subunit (concentrated on hippocampal somatostatin interneurons). RESULTS: We demonstrate – in the spatial memory task, during memory recall – that theta power increases in left medial temporal lobe (mTL) are impaired in Scz, as is theta phase coupling between mPFC and mTL. Importantly, the latter cannot be explained by theta power changes, head movement, antipsychotics, cannabis use, or IQ, and is not found in other frequency bands. Moreover, mPFC-mTL theta coupling correlated strongly with performance in controls, but not in Scz, who were mildly impaired at the spatial memory task and no better than chance on the memory integration task. Use of antipsychotic medication may ameliorate this mPFC-HC theta coupling deficit. Finally, mTL regions showing reduced theta phase coupling in Scz MEG participants overlapped substantially with areas of diminished α5-GABAAR availability in the wider Scz PET sample. DISCUSSION: These results indicate that impaired theta phase coupling between hippocampus and mPFC could underlie hippocampal-prefrontal dysconnectivity in schizophrenia, and impairments in the cognitive domains that depend on communication between these areas. They also imply α5-GABAARs (and the cells that express them) have a role in the phase coupling process.