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.

Fig. 1

GluA1 KO mice show reduced social behavior in non-habituated, but not in habituated, tests contexts. (A) Schematic of experimental design. (B) GluA1 KO mice engaged in less social interaction with a novel conspecific mouse than WT controls during the pre-habituation but not the post-habitation test. Social interaction increased from the pre- to post-habituation conditions in GluA1 KO mice but not WT controls (n = 44–46 per genotype). (C) Schematic of experimental design. (D) GluA1 KO mice display a trend to engage in less social interaction than WT controls in a non-habituated context, but engage is significantly more social exploration in a habituated test context. Levels of social interaction increased from the pre- to post-habituation conditions in GluA1 KO mice but not WT controls (n = 9–12 per genotype). Data are Means ± SEM. *p < .05 KO vs. WT, #p < 0.05 KO pre-habituation vs. post-habituation.

Fig. 2

GluA1 KO mice show faster acquisition and impaired extinction of reward-seeking behavior. (A) GluA1 KO mice required fewer trials than WT controls to acquire a stimulus-response behavior. (B) Stimulus response and reward-retrieval latency was not different between genotypes during acquisition. (C) GluA1 KO mice made significantly more non-rewarded responses than WT during the first 3 session of extinction training. (D) GluA1 KO mice failed to show significant within-session extinction during the first extinction session, and made significantly more non-rewarded responses than WT controls during the first and last trial-blocks during the second and third extinction sessions. n = 34–35 per genotype. Data are Means ± SEM. **p < .01, *p < .05 vs. WT, #p < .05 vs. Trial-block 1.

Fig. 3

GluA1 KO mice show slightly faster reversal learning. (A) KO required significantly fewer trials than WT to complete the early stage of reversal (=correct performance < 50%) when perseverative responding is relatively high. (B) KO made significantly fewer errors than WT during the early reversal stage. (C) Correction errors were not significantly different between genotypes during the early reversal stage. (D) Stimulus-reaction time and reward-retrieval latency did not differ between genotypes. n = 8–10 per genotype. Data are means ± SEM. *p < .05 vs. WT.

Fig. 4

GluA1 KO mice show increased impulsive choice in a delay-based cost/benefit decision-making task. (A) T-maze apparatus. Mice were placed in the start arm of the T-maze and allowed to choose (Gates A open) between the 2 visually-distinct goal arms, associated with either a high- (HR) or low- (LR) milk reward. On entry into an arm, Gate A was immediately closed and a forced waiting period (5–15 s for HR arm, 0 s for LR arm) imposed before Gate B was opened to allow access to the reward. (B) GluA1 KO mice and WT controls exhibited preference for the HR arm over 6-training sessions (0 delay for HR arm). In both genotypes, HR arm preference was maintained at a 5 s delay and slightly reduced at a 10 s delay. At a 15 s delay, GluA1 KO mice showed less HR-arm preference than WT controls. When both arms were HR at the 15 s delay, genotypes did not differ, but GluA1 KO mice again showed less HR arm preference when the 15 s delay was reinstated. n = 15–20 per genotype. Data are Means ± SEM. **p < .01 WT vs. KO.