Abstract
Schizophrenia is a chronic neurological disorder that causes significant impairment for ~1% of the population. Epidemiological studies have suggested that there is a link between prenatal exposure to infection and the development of schizophrenia in the progeny. In particular, maternal immune activation (MIA) in response to infection is thought to alter neurodevelopment so as to increase the risk of schizophrenia. The MIA animal model provides a useful platform to examine this link, as it separates the effects of infectious factors from immune activation. Here, the effects of MIA in the rat are characterized, with a particular focus on memory function and contextual processing, as these have been proposed to be core features of the cognitive symptoms of the disease. The contributions of the hippocampus to cognitive impairment in schizophrenia are also explored.
MIA was induced in pregnant rat dams on gestational day 15 with a single injection of the synthetic cytokine inducer poly I:C. Open-field exploration and pre-pulse inhibition (PPI) were assessed in juvenile (35 day) and adult (> 3 month) offspring. Discrimination and reversal learning, memory function and contextual processing were assessed in adult animals. A separate group of adult animals were implanted with electrodes in the dorsal hippocampus for an in vivo examination of hippocampal place cell activity.
MIA offspring were shown to display impaired PPI during testing conducted in adolescence and in adulthood. The MIA animals were also found to display abnormally rapid reversal learning of a position discrimination. MIA also resulted in memory impairment, with MIA animals displaying significantly reduced preferences for the novel object during recognition testing, and an increased memory for the reversed platform position in the Morris water maze task. MIA offspring also displayed evidence of impaired contextual processing, showing a reduced and less persistent reinstatement of rearing after a change in environmental context. The in vivo examination of hippocampal place cell activity indicated that cells in MIA offspring display a more spatially selective representation of 'place' than control cells. MIA animals were also less likely to shut down or turn on their spatial firing in one of the environmental contexts, indicative of reduced context specificity.
Here it is demonstrated that MIA in the rat produces behaviours that are similar to the positive and cognitive symptoms seen in patients with schizophrenia. We have demonstrated for the first time that MIA results in a similar disruption of sensorimotor-gating and non-spatial memory in the adult rat, as has previously been reported for mice. Interestingly, we found that PPI impairments in the rat do not display the same post-pubertal pattern of emergence that is seen after MIA in the mouse. We have also shown for the first time that MIA is associated with impaired contextual processing, a disruption that is thought to be a core underlying deficit in schizophrenia. The examination of hippocampal place cell activity also suggested a reduced sensitivity to contextual information in the MIA animals. These results suggest reduced context-specificity of hippocampal representations may be a factor underlying contextual processing impairments in schizophrenia.