Impaired Reality Testing in Mice Lacking Phospholipase Cβ1: Observed by Persistent Representation-Mediated Taste Aversion

Abstract

Hallucinations and delusions are the most prominent symptoms of schizophrenia and characterized by impaired reality testing. Representation-mediated taste aversion (RMTA) has been proposed as a potential behavioral assessment of reality testing and has been applied to a neurodevelopmental rat model of schizophrenia. However, the theory underlying this approach has not been generalized yet with any demonstration of impaired reality testing in other animal models of schizophrenia, such as genetically-modified mice. We devised a RMTA procedure for mice that combines a Pavlovian association protocol pairing odor conditioned stimulus (CS) with sugar reward unconditioned stimulus (US), and a conditioned taste aversion (CTA) method. In this RMTA paradigm, we compared performances of wild-type (PLCβ1+/+) mice and phospholipase C β1 knock-out (PLCβ1-/-) mice which are known as one of the genetic models for schizophrenia. With a minimal amount of initial odor-sugar associative training, both PLCβ1+/+ and PLCβ1-/- mice were able to form an aversion to the sugar reward when the odor CS predicting sugar was paired with nausea. With an extended initial training, however, only PLCβ1-/- mice could form a RMTA. This persistent RMTA displayed by PLCβ1-/- mice shows their inability to distinguish real sugar from the CS-evoked representation of sugar at a stage in associative learning where wild-type mice normally could differentiate the two. These results demonstrate an impaired reality testing first observed in a genetic mouse model of schizophrenia, and suggest that RMTA paradigm may, with general applicability, allow diverse biological approaches to impaired reality testing.

Stimulation of phospholipase Cβ1 by Gαq promotes the assembly of stress granule proteins

“…It is notable that PLCβ1 is highly expressed in neuronal tissue (48) and reduced levels are associated with a host of neurological disorders that may result from disruptions in calcium signaling, neuronal cells proliferation and differentiation (e.g. (49)(50)(51)(52). Schizophrenia and suicide has been shown to specifically involve varying levels of PLCβ1a and 1b in the prefrontal cortex (51).…”

Pregnenolone blocks cannabinoid-induced acute psychotic-like states in mice

“…However, after 6 or 9 odor-taste pairings (long training) control animals did not show mediated aversion, suggesting that they are able to separate the values of CS+ and mCS+. Considering that CS+ and mCS+ are separated in reality, this phenomenon is generally called “reality testing” in the literature ( 29 – 31 ), and we use this term in the present study. Thus, conditions or treatments that restore mediated aversion are considered as alteration of “reality testing”, in a way that reasonably approximate “erroneous beliefs that usually involve a misinterpretation of perception or experiences” typically observed in patients experiencing positive psychotic symptoms ( 35 – 36 ).…”

“…decreased PPI) and reduction of social interaction in mice. Moreover, we adapted a behavioral approach recently proposed in rodents ( 29 – 31 ) to study alterations in mental sensory representations which are hallmarks of positive psychotic-like states. The results show that pregnenolone can block the full range of acute psychotic-like symptoms and related endophenotypes induced by THC, thereby suggesting that drugs mimicking pregnenolone activity could be used to treat CIAPS.…”

Representation-mediated Aversion as a Model to Study Psychotic-like States in Mice

“…For instance, the ‘Diagnostic and Statistical Manual of Mental Disorders’ (DSM V) defines delusions as ‘erroneous beliefs that usually involve a misinterpretation of perception or experiences’ (American Psychiatric Association, 2013). To overcome this methodological limitation, recent studies have used behavioral procedures in rodents designed to measure the accuracy of mental representations of reality, also called ‘reality testing’ (McDannald and Schoenbaum, 2009; McDannald et al ., 2011; Kim and Koh, 2016). Alterations in ‘reality testing’ performance can be an indication of an impairment in perception which, as we mentioned before, might lead to positive psychotic-like states such as delusions.…”

“…Alterations in ‘reality testing’ performance can be an indication of an impairment in perception which, as we mentioned before, might lead to positive psychotic-like states such as delusions. Thus, we adapt these previous protocols (McDannald and Schoenbaum, 2009; McDannald et al ., 2011; Wheeler et al ., 2013; Kim and Koh, 2016) to design a behavioral paradigm for measuring ‘reality testing’ in mice (Busquets-Garcia et al ., 2017). Notably, deficits in task performance induced by psychotogenic drugs ( e.g ., amphetamine or cannabinoids) seem to reflect the kind of perceptual alterations that are the hallmarks and early features of positive psychotic-like symptoms.…”