Constitutive loss and acute pharmacological manipulation of ErbB4 signaling do not affect attention and inhibitory control in mice

Abstract

The receptor tyrosine kinase ErbB4 and its ligand trophic factors of the neuregulin (NRG) family have been associated with schizophrenia and other mental disorders in human genetic studies. In vivo studies in mice have shown how abnormal Nrg-ErbB4 signaling leads to deviant behaviors relevant to distinct aspects of schizophrenia, including hyperactivity, sensory gating deficits, working and spatial memory deficits and impaired social behavior. However, so far little is known on the role of ErbB4 in attention and inhibitory control, two aspects of executive functions that are impaired in schizophrenia. Here we investigated the effects of constitutive loss of ErbB4 in the central nervous system of mice on performance in a 5-choice serial reaction time task (5CSRTT) assessing attention and inhibitory control. In this task, ErbB4 mice did not show deficits in various parameters of attention, and premature responses as measure of inhibitory control. Nonetheless, ErbB4 mice recapitulated a specific set of behavioral phenotypes associated with schizophrenia, including a deficit in spatial learning and memory in the Barnes Maze and in contextual fear learning, and a trend for a deficit in sensorimotor gating. Furthermore, we investigated the effect of acute pharmacological inhibition of ErbB tyrosine kinase receptor using the pan-ErbB kinase inhibitor JNJ-28871063 (JNJ), in an automated version of the 5CSRTT. JNJ did not affect attention and inhibitory control. In conclusion, our data suggest no direct involvement of a classical Nrg-ErbB4 pathway in attention and inhibitory control in mice, while it confirms the involvement of this pathway in other domains relevant to schizophrenia.

ErbB4 Null Mice Display Altered Mesocorticolimbic and Nigrostriatal Dopamine Levels as well as Deficits in Cognitive and Motivational Behaviors

“…The reversed U-shaped curve in response to amphetamine is consistent with previous work showing that that high doses of amphetamine resulted in stereotypical behaviors, rather than elevated horizontal locomotor activity (Segal, 1975). Moreover, these findings are also consistent with prior studies reporting ErbB4 KO mice are hyperactive when exposed to novel environments and to augmented basal levels of striatal DA in KOs (Shamir et al, 2012;Marchisella et al, 2018). ErbB4 KO mice exhibit deficits in spatial learning memory Numerous studies in humans (Egan et al, 2001;Cools and D'Esposito, 2011), non-human primates (Arnsten et al, 1994;Williams and Goldman-Rakic, 1995), and rodents (Spellman et al, 2015;Cassidy et al, 2016) have shown the importance of an "inverted U-shape" relationship between optimal DA levels in PFC and performance on cognitive-related tasks.…”

“…The findings presented here and earlier studies emphasize the importance of NRG/ErbB4 signaling for cognitive functions (Wen et al, 2010;Shamir et al, 2012;Loos et al, 2014Loos et al, , 2016Marchisella et al, 2018;Skirzewski et al, 2018;Yan et al, 2018). Specifically, we found that ErbB4 KO mice show behavioral deficits that suggest impairments in declarative (NOR; Fig.…”