Behavioral Characterization of Transgenic Mice for Renin-Angiotensin and Bradykinin System: Implications for Neurodevelopmental Disorders?

The high prevalence of cardiovascular diseases (CVDs) and neurodevelopmental disorders (NDDs) is gaining increasing attention. Classically recognized for its cardiovascular role, the renin-angiotensin system (RAS) - bradykinin axis has increasingly been implicated in the pathophysiology of NDDs, such as autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and schizophrenia. The RAS-bradykinin axis is governed by the interplay between angiotensin I - converting enzyme (ACE) activity and bradykinin B2 receptor (B2R) signaling, a relationship that modulates the shift between detrimental vasoconstrictive states and beneficial, neuroprotective vasodilation. ACE is responsible for the conversion of Ang I into the hypertensive peptide Ang II while also being able to cleave and silence the hypotensive peptide bradykinin. In this study, we used genetically modified mice for transgenic ACE (carrying either three or one functional copy of the ACE gene) and B2R null knockout mice to determine the impact on behavioral domains relevant to NDDs of increased ACE and/or B2 receptor deletion. Three-month-old transgenic mice carrying three copies of the ACE gene showed increased locomotor activity, as well as social and cognitive deficits compared to wild-type animals. B2R knockout mice displayed sensorimotor gating dysfunction. Our results further support the involvement of the RAS-bradykinin axis in neurodevelopment and in behavioral measures relevant to NDDs. Overall, our present data suggest specific alterations in these physiological systems may lead to different behavioral abnormalities in mice. These findings highlight the need for future mechanistic investigations and contribute to a clearer understanding of the comorbidity between CVDs and NDDs.