Do GluA1 knockout mice exhibit behavioral abnormalities relevant to the negative or cognitive symptoms of schizophrenia and schizoaffective disorder?

Abstract

The glutamate system has been strongly implicated in the pathophysiology of psychotic illnesses, including schizophrenia and schizoaffective disorder. We recently found that knockout (KO) mice lacking the AMPA GluA1 subunit displayed behavioral abnormalities relevant to some of the positive symptoms of these disorders. Here we phenotyped GluA1 KO mice for behavioral phenotypes pertinent to negative and cognitive/executive symptoms. GluA1 KO mice were tested for conspecific social interactions, the acquisition and extinction of an operant response for food-reward, operant-based pairwise visual discrimination and reversal learning, and impulsive choice in a delay-based cost/benefit decision-making T-maze task. Results showed that GluA1 KO mice engaged in less social interaction than wildtype (WT) controls when tested in a non-habituated, novel environment, but, conversely, displayed more social interaction in a well habituated, familiar environment. GluA1 KO mice were faster to acquire an operant stimulus-response for food reward than WT and were subsequently slower to extinguish the response. Genotypes showed similar pairwise discrimination learning and reversal, although GluA1 KO mice made fewer errors during early reversal. GluA1 KO mice also displayed increased impulsive choice, being less inclined to choose a delayed, larger reward when given a choice between this and a smaller, immediate reward, compared to WT mice. Finally, sucrose preference did not differ between genotypes. Collectively, these data add to the growing evidence that GluA1 KO mice display at least some phenotypic abnormalities mimicking those found in schizophrenia/schizoaffective disorder. Although these mice, like any other single mutant line, are unlikely to model the entire disease, they may nevertheless provide a useful tool for studying the role of GluA1 in certain aspects of the pathophysiology of major psychotic illness.

Stress facilitates late reversal learning using a touchscreen-based visual discrimination procedure in male Long Evans rats

“…1) whereas the other studies gave three daily sessions of stress before initiating reversal learning [11,12]. One study also found that a single bout of swim stress had no effect on the first session of reversal learning in wild-type and GluA1 knockout mice using a touchscreen-based task [20], which is consistent with our findings. Together, these results suggest that stress has a delayed impact on reversal learning in rats and mice.…”

“…A second study using a task design similar to Thai and colleagues [10] found no effect of an in-context tail pinch stressor on reversal learning [7]. In addition, Barkus and colleagues assessed the effects of acute swim stress on a single reversal learning session of a touchscreen-based visual discrimination in mice [20]. They found no effect of acute swim stress on early reversal learning in either GluA1 knockout mice or their wild type controls (>75% C57BL/6J background).…”

Adult AMPA GLUA1 Receptor Subunit Loss in 5-HT Neurons Results in a Specific Anxiety-Phenotype with Evidence for Dysregulation of 5-HT Neuronal Activity

“…They also show mild deficits in motor coordination (Bannerman et al, 2004) and massive novelty induced hyperlocomotion (Bannerman et al, 2004;Chourbaji et al, 2008c;Vekovischeva et al, 2001). Global Gria1-knockout mice have also been shown to exhibit increased learned helplessness (Chourbaji et al, 2008c) as well as mania-and schizophrenia-related behavioral abnormalities (Barkus et al, 2012;Fitzgerald et al, 2010;Wiedholz et al, 2008). The involvement of many different GLUA1-deficient neuronal populations probably underlies the observed complex phenotype.…”

“…Indeed under these circumstances, it is virtually impossible to infer the specific neuronal population responsible for any identified behavioral 'symptom'. Hence, it is not surprising that complex and conflicting results for anxiety-related behavior have also been reported in global Gria1-knockouts (Barkus et al, 2012). Increased anxiety-like behavior has been shown in the hyponeophagia test (Bannerman et al, 2004), while reduced anxiety-like behavior was found in the elevated plus maze and Dark-Light Box (Fitzgerald et al, 2010;Vekovischeva et al, 2004).…”

“…Increased anxiety-like behavior has been shown in the hyponeophagia test (Bannerman et al, 2004), while reduced anxiety-like behavior was found in the elevated plus maze and Dark-Light Box (Fitzgerald et al, 2010;Vekovischeva et al, 2004). This apparent inconsistency could be a result of the impaired short-term habituation and novelty induced hyperlocomotion in global Gria1-knockouts that complicate analysis of anxiety behavior (Barkus et al, 2012;Chourbaji et al, 2008c;Wiedholz et al, 2008).…”