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

Abstract

Natural genetic variants of Neuregulin1 (NRG1) and its cognate receptor ErbB4 are associated with a risk for schizophrenia. Whereas most studies on NRG1-ErbB4 signaling have focused on GABAergic interneurons, ErbB4 is also expressed by midbrain dopaminergic neurons where it modulates extracellular dopamine (DA) levels. Here, we report that extracellular steady-state levels of DA are reduced in the medial prefrontal cortex (mPFC; À65%), hippocampus (À53%) and nucleus accumbens (NAc; À35%), but are elevated in the dorsal striatum (125%) of ErbB4 knock-out mice (ErbB4 KOs) relative to wild-type controls. This pattern of DA imbalance recapitulates the reported prefrontal cortical reduction and striatal increase of DA levels in schizophrenia patients. Next, we report on a battery of behavioral tasks used to evaluate locomotor, cognitive and motivational behaviors in ErbB4 KOs relative to controls. We found that ErbB4 KOs are hyperactive in a novel open field but not in their familiar home cage, are more sensitive to amphetamine, perform poorly in the T-maze and novel object recognition (NOR) tasks, exhibit reduced spatial learning and memory on the Barnes maze, and perform markedly worse in conditioned place preference (CPP) tasks when associating cued-reward palatable food with location. However, we found that the poor performance of ErbB4 KOs in CPP are likely due to deficits in spatial memory, instead of reward seeking, as ErbB4 KOs are more motivated to work for palatable food rewards. Our findings indicate that ErbB4 signaling affects tonic DA levels and modulates a wide array of behavioral deficits relevant to psychiatric disorders, including schizophrenia.

Developmental, neurochemical, and behavioral analyses of ErbB4 Cyt‐1 knockout mice

“…Later in development, NRG/ErbB4 signaling regulates the maturation of glutamatergic synapses onto GABAergic interneurons (Del Pino et al, 2013; Fazzari et al, 2010; Kotzadimitriou et al, 2018; Vullhorst et al, 2015; Woo et al, 2007; Yang et al, 2013; Yang et al, 2018), particularly parvalbumin (PV)‐positive fast‐spiking interneurons, that modulate critical period plasticity (Gu et al, 2016; Sun et al, 2016) and neuronal network activity (Andersson et al, 2012; Fisahn et al, 2009; Nason Jr. et al, 2011). NRG/ErbB4 signaling in midbrain DAergic neurons also regulates DA homeostasis and cognitive function (Kwon et al, 2008; Namba et al, 2016; Skirzewski et al, 2018; Skirzewski et al, 2020; Yan et al, 2018). Interestingly, both NRG2 and ErbB4 KOs, as well as conditional ErbB4 fl/fl mutant mice that lack the receptor in tyrosine hydroxylase (Th)‐expressing neurons (Th‐Cre; ErbB4 fl/fl ), exhibit imbalances of basal extracellular DA levels in distinct projection areas (Kato et al, 2011; Mizuno et al, 2013; Skirzewski et al, 2018; Skirzewski et al, 2020; Yan et al, 2018) that are reminiscent of the imbalances in DA release reported in the dorsal striatum and dorsolateral prefrontal cortex (DLPFC) of Scz patients (Slifstein et al, 2015; Weinstein et al, 2017).…”

“…NRG/ErbB4 signaling in midbrain DAergic neurons also regulates DA homeostasis and cognitive function (Kwon et al, 2008; Namba et al, 2016; Skirzewski et al, 2018; Skirzewski et al, 2020; Yan et al, 2018). Interestingly, both NRG2 and ErbB4 KOs, as well as conditional ErbB4 fl/fl mutant mice that lack the receptor in tyrosine hydroxylase (Th)‐expressing neurons (Th‐Cre; ErbB4 fl/fl ), exhibit imbalances of basal extracellular DA levels in distinct projection areas (Kato et al, 2011; Mizuno et al, 2013; Skirzewski et al, 2018; Skirzewski et al, 2020; Yan et al, 2018) that are reminiscent of the imbalances in DA release reported in the dorsal striatum and dorsolateral prefrontal cortex (DLPFC) of Scz patients (Slifstein et al, 2015; Weinstein et al, 2017). Consistent with the association of the NRG/ErbB4 signaling pathway with a risk for Scz, mice with targeted mutations in either nrg1 , nrg2 , nrg3 , or erbb4 manifest many behavioral abnormalities that are associated with traits observed in Scz (Chen et al, 2010; Hayes et al, 2016; Lu et al, 2014; Muller et al, 2018; Shamir et al, 2012; Skirzewski et al, 2018; Tan et al, 2018; Wen et al, 2010; Yan et al, 2018), and in some studies shown to be ameliorated by antipsychotic treatment (Tan et al, 2018; Yan et al, 2018).…”

In trans neuregulin3-Caspr3 interaction controls DA axonal bassoon cluster development

“…Caspr3 interaction in trans with NRG3 NRG3 is a ligand that binds to and activates ErbB4; 37 however, ErbB4 activation has been implicated to increase DA transmission. 38 ErbB4 null mutation seemed to have little effect on DA axonal BSN clusters and axon branches in NAcc (Figures S4A-S4D). These observations suggest that NRG3 regulates DA synapses and transmission in an ErbB4-independent mechanism.…”

“…On the contrary, NRG1-ErbB4 signaling was shown to increase DA release; DA levels in the PFC and striatum were reduced in ErbB4 null mice. 38,51 These observations suggest that NRG3 regulates DA synapses in a mechanism independent of ErbB4. Non-based screens for NRG3 binding proteins from a library consisting of many transmembrane molecules implicated in synaptogenesis identified Caspr3 and ErbB4.…”

Polycystic Ovary Syndrome and Risk of Five Common Psychiatric Disorders Among European Women: A Two-Sample Mendelian Randomization Study

“…Some SNPs among the PCOS-IVs in the present study play roles in neurotransmitter systems. For instance, rs2178575 lies in an intron of the gene encoding Erb-B2 receptor tyrosine kinase 4 (ERBB4), which is expressed in GABAergic interneurons but also in midbrain dopaminergic neurons, where it regulates dopamine levels by binding to neuregulin 1 (NRG1) (Skirzewski et al, 2020 ). Mice lacking ErbB4 show regional imbalances in basal dopamine levels and fail to increase dopamine release in response to local NRG1 infusion in the dorsal hippocampus, medial pre-frontal cortex and dorsal striatum (Skirzewski et al, 2018 ).…”