Abstract
Animal models of schizophrenia-relevant symptoms are increasingly important for progress in our understanding of the neurobiological basis of the disorder and for discovering novel and more specific treatments. Prepulse inhibition (PPI) and working memory, which are impaired in schizophrenic patients, are among the symptoms/processes modeled in those animal analogs. We have evaluated whether a genetically-selected rat model, the Roman high-avoidance inbred strain (RHA-I), displays PPI deficits as compared with its Roman low-avoidance (RLA-I) counterpart and the genetically heterogeneous NIH-HS rat stock. We have investigated whether PPI deficits predict spatial working memory impairments (in the Morris water maze; MWM) in these three rat types (Experiment 1), as well as in a separate sample of NIH-HS rats stratified according to their extreme (High, Medium, Low) PPI scores (Experiment 2). The results from Experiment 1 show that RHA-I rats display PPI and spatial working memory deficits compared to both RLA-I and NIH-HS rats. Likewise, in Experiment 2, “Low-PPI” NIH-HS rats present significantly impaired working memory with respect to “Medium-PPI” and “High-PPI” NIH-HS subgroups. Further support to these results comes from correlational, factorial, and multiple regression analyses, which reveal that PPI is positively associated with spatial working memory performance. Conversely, cued learning in the MWM was not associated with PPI. Thus, using genetically-selected and genetically heterogeneous rats, the present study shows, for the first time, that PPI is a positive predictor of performance in a spatial working memory task. These results may have translational value for schizophrenia symptom research in humans, as they suggest that either by psychogenetic selection or by focusing on extreme PPI scores from a genetically heterogeneous rat stock, it is possible to detect a useful (perhaps “at risk”) phenotype to study cognitive anomalies linked to schizophrenia.
Highlights
Schizophrenia symptoms are usually grouped in three categories: positive; negative and cognitive impairment
In keeping with the hypothesis that RHA-I rats could be a tool to discern cognitive peculiarities linked to some schizophreniarelated symptoms, we have found that this rat strain displays deficits in prepulse inhibition (PPI) and in spatial working memory compared with RLA-I and NIH-HS rats
It is shown for the first time that the genetically heterogeneous NIH-HS rat stock displays relatively high PPI levels as well as efficient spatial working memory, as their values in both processes/measures are similar to those shown by RLA-I rats
Summary
Schizophrenia symptoms are usually grouped in three categories: positive (hallucinations, delusions, and other thought disorders); negative (anhedonia, avolition, poverty of thought, and content of speech) and cognitive impairment (working memory and attention deterioration). Their complexity, diversity, and bizarreness preclude a full modeling of the entire constellation in animals, just as schizophrenic patients do not manifest every possible symptom. Some rat and mouse models may be used to assess sensorimotor gating (pre-attentive) or attention-related processes which are impaired in schizophrenic patients (e.g., reviews by Sawa and Snyder, 2002; Powell and Miyakawa, 2006; Jones et al, 2011; Del Río et al, 2014). PPI is impaired in schizophrenic patients, among other mental disorders, and it is widely considered an endophenotype of the disorder (e.g., reviews by Freedman et al, 1987; Koch and Schnitzler, 1997; Cromwell et al, 2008; García-Sánchez et al, 2011; Kohl et al, 2013)
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