Abstract
Schizophrenia is a chronic and debilitating disorder in which patients display deficits in many cognitive functions, including spatial and sequential memory. Animals that have experienced maternal immune activation (MIA) or ketamine injections show similar cognitive deficits to people with schizophrenia. These animal models are used to explore the neural mechanism which may underlie the cognitive symptoms of schizophrenia, as they are currently challenging to study in humans.
The hippocampus is a brain region involved in learning and memory, particularly spatial memory; therefore, it is an area that may be involved in schizophrenia. One neural mechanism in the hippocampus which assists in storing spatial and sequential information is phase precession. Phase precession is a systematic shift in spike timing against the underlying neural activity, such as theta rhythm and sharp wave ripples (SWRs). When phase precession from multiple cells is combined, sequences encoding spatial information occur. The disordered sequencing which results from disruptions to phase precession may explain some of the cognitive symptoms associated with schizophrenia.
Recently, disruptions to theta phase precession have been detected in an MIA model of schizophrenia. It is unknown if this finding holds up in a ketamine model of schizophrenia. Phase precession also occurs within SWRs in the hippocampus, although the function of this phenomenon is unknown. Studies have yet to explore whether SWR phase precession is disrupted in animal models of schizophrenia. The present study had two experiments. The first experiment aimed to examine the effects of ketamine administration on theta phase precession, place cell firing, and SWRs. The second experiment aimed to determine if SWR phase precession was affected in MIA and ketamine of schizophrenia.
In brief, extracellular single-unit and electroencephalography data were obtained from data captured by various researchers. Data were obtained from 28 Sprague Dawley rats (11 naïve, nine MIA, and eight control) through two tetrodes and an LFP wire implanted in the CA1 layer of the hippocampus. The results of Experiment 1 suggested disruptions to theta phase precession occur after ketamine administration, particularly the magnitude of phase precession, firing rate, amplitude, and speed at the spike. There was no significant difference in the power or frequency of SWRs when comparing ABA trials. The results of Experiment 2 suggested that SWR phase precession was disrupted by ketamine administration, particularly the starting phase. The results also indicated that SWR phase precession is disrupted in an MIA model of schizophrenia, particularly relating to changes in the correlation of phase precession, slope, amplitude envelope, and starting phase of SWR phase precession.
The results of Experiment 1 suggest that ketamine may disrupt theta phase precession through alterations to NMDA receptors within the hippocampus, which may alter the magnitude of phase precession. The results of Experiment 2 provide preliminary evidence for a relationship between place cell spiking over time and SWRs. They also suggest that this SWR phase precession is disrupted in ketamine and MIA models of schizophrenia. Disruptions to both theta and SWR phase precession may explain the temporal and spatial disorganisation observed in people with schizophrenia.