Hippocampal Sequencing Mechanisms Are Disrupted in a Maternal Immune Activation Model of Schizophrenia Risk.

Episodic memory requires information to be stored and recalled in sequential order, and these processes are disrupted in schizophrenia. Hippocampal phase precession and theta sequences are thought to provide a biological mechanism for sequential ordering of experience at timescales suitable for plasticity. These phenomena have not previously been examined in any models of schizophrenia risk. Here, we examine these phenomena in a maternal immune activation (MIA) rodent model. We show that while individual pyramidal cells in the CA1 region continue to precess normally in MIA animals, the starting phase of precession as an animal enters a new place field is considerably more variable in MIA animals than in controls. A critical consequence of this change is a disorganization of the ordered representation of experience via theta sequences. These results provide the first evidence of a biological-level mechanism that, if it occurs in schizophrenia, may explain aspects of disorganized sequential processing that contribute to the cognitive symptoms of the disorder.SIGNIFICANCE STATEMENT Hippocampal phase precession and theta sequences have been proposed as biophysical mechanisms by which the sequential structure of cognition might be ordered. Disturbances of sequential processing have frequently been observed in schizophrenia. Here, we show for the first time that phase precession and theta sequences are disrupted in a maternal immune activation (MIA) model of schizophrenia risk. This is a result of greater variability in the starting phase of precession, indicating that the mechanisms that coordinate precession at the assembly level are disrupted. We propose that this disturbance in phase precession underlies some of the disorganized cognitive symptoms that occur in schizophrenia. These findings could have important preclinical significance for the identification and treatment of schizophrenia risk factors.