Altered Cortical Ensembles in Mouse Models of Schizophrenia

In schizophrenia, brain-wide alterations have been identified at the molecular and cellular levels, yet how these phenomena affect cortical circuit activity remains unclear. We studied two mouse models of schizophrenia-relevant disease processes: chronic ketamine (KET) administration and Df(16) A(+/-), modeling 22q11.2 microdeletions, a genetic variant highly penetrant for schizophrenia. Local field potential recordings in visual cortex confirmed gammaband abnormalities similar to patient studies. Twophoton calciumimaging of local cortical populations revealed in both models a deficit in the reliability of neuronal coactivity patterns (ensembles), which was not a simple consequence of altered singleneuron activity. This effect was present in ongoing and sensory-evoked activity and was not replicated by acute ketamine administration or pharmacogenetic parvalbumin-interneuron suppression. These results are consistent with the hypothesis that schizophrenia is an `` attractor'' disease and demonstrate that degraded neuronal ensembles are a common consequence of diverse genetic, cellular, and synaptic alterations seen in chronic schizophrenia.