Neuronal activity in the prefrontal cortex (PFC) controls dominance hierarchies in groups of animals. Dopamine (DA) strongly modulates PFC activity mainly through D1 receptors (D1Rs) and D2 receptors (D2Rs). Still, it is unclear how these two subpopulations of DA receptor-expressing neurons in the PFC regulate social dominance hierarchy. Here, we demonstrate distinct roles for prefrontal D1R-and D2R-expressing neurons in establishing social hierarchy, with D1R 1 neurons determining dominance and D2R 1 neurons for subordinate. Ex vivo whole-cell recordings revealed that the dominant status of male mice correlates with rectifying AMPAR transmission and stronger excitatory synaptic strength onto D1R 1 neurons in PFC pyramidal neurons. In contrast, the submissive status is associated with higher neuronal excitability in D2R 1 neurons. Moreover, simultaneous manipulations of synaptic efficacy of D1R 1 neurons in dominant male mice and neuronal excitability of D2R 1 neurons of their male subordinates switch their dominant-subordinate relationship. These results reveal that prefrontal D1R 1 and D2R 1 neurons have distinct but synergistic functions in the dominance hierarchy, and DA-mediated regulation of synaptic strengths acts as a powerful behavioral determinant of intermale social rank.
Aims
Epidermal growth factor receptor (EGFR) is essential to the development of multiple tissues and organs and is a target of cancer therapeutics. Due to the embryonic lethality of global EGFR deletion and conflicting reports of cardiac-overexpressed EGFR mutants, its specific impact on the adult heart, normally or in response to chronic stress, has not been established. Using complimentary genetic strategies to modulate cardiomyocyte-specific EGFR expression, we aim to define its role in the regulation of cardiac function and remodelling.
Methods and results
A floxed EGFR mouse model with α-myosin heavy chain-Cre-mediated cardiomyocyte-specific EGFR downregulation (CM-EGFR-KD mice) developed contractile dysfunction by 9 weeks of age, marked by impaired diastolic relaxation, as monitored via echocardiographic, haemodynamic, and isolated cardiomyocyte contractility analyses. This contractile defect was maintained over time without overt cardiac remodelling until 10 months of age, after which the mice ultimately developed severe heart failure and reduced lifespan. Acute downregulation of EGFR in adult floxed EGFR mice with adeno-associated virus 9 (AAV9)-encoded Cre with a cardiac troponin T promoter (AAV9-cTnT-Cre) recapitulated the CM-EGFR-KD phenotype, while AAV9-cTnT-EGFR treatment of adult CM-EGFR-KD mice rescued the phenotype. Notably, chronic administration of the β-adrenergic receptor agonist isoproterenol effectively and reversibly compensated for the contractile dysfunction in the absence of cardiomyocyte hypertrophy in CM-EGFR-KD mice. Mechanistically, EGFR downregulation reduced the expression of protein phosphatase 2A regulatory subunit Ppp2r3a/PR72, which was associated with decreased phosphorylation of phospholamban and Ca2+ clearance, and whose re-expression via AAV9-cTnT-PR72 rescued the CM-EGFR-KD phenotype.
Conclusions
Altogether, our study highlights a previously unrecognized role for EGFR in maintaining contractile homeostasis under physiologic conditions in the adult heart via regulation of PR72 expression.
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