Genetic Rat Models of Schizophrenia-Relevant Symptoms

Abstract

It is recognized that developing valid animal models is essential for the research on the neurobiological mechanisms of (and treatments for) psychiatric disorders, even when these are as complex as schizophrenia. To be considered a valid analogue of the disorder, a given model should present good face validity (i.e. similarity of symptoms), good predictive validity (i.e. similarity of treatment effects and potential for discovering novel treatments) and enough construct validity (i.e. the model should help discover neurobiological mechanisms underlying the disorder or some relevant symptoms). The complexity of symptoms (positive, negative and cognitive) of schizophrenia makes it a very difficult task for a model to mimic all the main features of the disorder, but some rodent (mouse and rat) models have behavioural and even neurobiological phenotype characteristics resembling positive-like symptoms, cognitive symptoms and some neurochemical features of schizophrenia. As several recent works have already reviewed the main behavioural and developmental models, as well as the most used drug-induced, lesion-induced and genetic mouse models, the present review focuses on describing the most relevant genetically-based rat models of schizophrenia-relevant symptoms. Thus, we discuss several selective breeding programs leading to rat lines/strains which present impaired prepulse inhibition (PPI) of the acoustic startle response and (in some cases) latent inhibition deficits (both of which may be considered as endophenotypes of schizophrenia related with pre-attentive processes and attention, respectively), as well as other schizophrenia-relevant symptoms (e.g. learning deficits). Evidence is presented for the effects of genetic background on PPI (and other symptoms/phenotypes), as well as for environmental influences on genetic predisposition to enhanced apomorphine (mixed dopamine receptor agonist) effects. Some of the described rat models appear to present face validity and, to a certain extent, construct validity. While efforts should be made to evaluate the predictive validity of these genetic rat models, we propose that they have the advantage (over mouse knockouts, for example) of better representing "normal" genetic, neurobiological and phenotype variation, * Corresponding author.C. del Río et al. 262thus allowing the study of associations among them by means of genetic mapping or gene expression studies.

A Genetic Model of Impulsivity, Vulnerability to Drug Abuse and Schizophrenia-Relevant Symptoms With Translational Potential: The Roman High- vs. Low-Avoidance Rats

“…In line with these strain-related differences in LI, we have shown in a series of studies that RHA rats display clear and consistent deficits of PPI of the acoustic startle response compared with RLAs (Del Rio et al, 2014; Oliveras et al, 2015, 2016, 2017; Río-Alamos et al, 2015; Río-Álamos et al, 2017a,b, 2019; Tapias-Espinosa et al, 2018, 2019) and that PPI deficits predict spatial working memory impairments (Oliveras et al, 2015). Altogether, the above mentioned cognitive and attentional profiles of RHA vs. RLA rats suggest that the former may represent a model of schizophrenia-relevant features.…”

“…Altogether, the above mentioned cognitive and attentional profiles of RHA vs. RLA rats suggest that the former may represent a model of schizophrenia-relevant features. This is further supported by the increased mesolimbic/mesostriatal dopaminergic functional tone of RHA rats (Giorgi et al, 2007; Tournier et al, 2013), their enhanced sensitivity to the locomotor and DA releasing effects of acute and chronic psychostimulants (Corda et al, 2005; Giorgi et al, 2005a,b, 2007; Guitart-Masip et al, 2008), and by the finding that, relative to RLA rats, RHAs exhibit some impairments in social behavior (Coppens et al, 2012; Del Rio et al, 2014).…”

“…Remarkably, compared with RLAs, RHA rats display an impulsive phenotype, as shown by their response profiles in the delayed response latency 20 (DRL-20), schedule-induced polydipsia, and 5-choice serial reaction time (5CSRT) tasks (Zeier et al, 1978; Moreno et al, 2010; Merchán et al, 2019; see “The Roman Rats: A Genetic Model of Differential Anxiety, Novelty Seeking, Impulsivity, Attention Deficits and Associated Traits” section). Moreover, relative to RLAs, RHA rats display several impairments in schizophrenia-relevant phenotypes, such as prepulse inhibition (PPI; Oliveras et al, 2015; Río-Álamos et al, 2019), latent inhibition (LI; Fernández-Teruel et al, 2006), spatial working memory (Oliveras et al, 2015) and reversal learning (Río-Álamos et al, 2019) as well as a trend towards a reduction of some types of social behavior (Coppens et al, 2012; Del Rio et al, 2014; see “RHA Rats as a Model of Deficits in Attentional Processes, Cognitive Impairments and Other Features Relevant for Schizophrenia Research” section). These behavioral profiles are consistent with findings of a reduced volume and function of the medial prefrontal cortex (mPFCx), hippocampus (HC) and amygdala (AMY) of RHA vs. RLA rats (Río-Álamos et al, 2017a, 2019).…”

Roman high and low avoidance rats differ in their response to chronic olanzapine treatment at the level of body weight regulation, glucose homeostasis, and cortico-mesolimbic gene expression

“…Furthermore, the increased OLZ-induced weight and adiposity accumulation in the RHA strain was associated with a reduction in glucose tolerance during an IVGTT, an effect that was not observed in the RLA strain. Thus, our findings demonstrate that rats of the RHA strain, which represents a rat model for schizophrenia (Corda et al, 1997; D’Angio et al, 1988; Driscoll, 1986; Oliveras et al, 2015; Río et al, 2014; Steimer et al, 1997), experience more profound metabolic side-effects from treatment with the antipsychotic OLZ than those of the RLA strain.…”

“…During the last decades, tremendous advancements have been made in understanding the neurobiology of psychogenetic diseases, in part by using animal models reflecting disease etiology and/or disease end-points (Degen et al, 2005; Ellenbroek et al, 1995). The Roman high and low avoidance (RHA/RLA) rat strains, for instance, have been instrumental in unraveling neuronal pathways underlying certain behaviors reflected in schizophrenia (Río et al, 2014). Despite the fact that the selection of these strains is based on high or low active avoidance performance in a shuttle-box, the two selection strains are additionally characterized by several behavioral differences.…”