title: Increasing brain angiotensin converting enzyme 2 activity decreases anxiety-like behavior in male mice by activating central Mas receptors.
abstract: Over-activation of the brain renin-angiotensin system (RAS) has been implicated in the etiology of anxiety disorders. Angiotensin converting enzyme 2 (ACE2) inhibits RAS activity by converting angiotensin-II, the effector peptide of RAS, to angiotensin-(1-7), which activates the Mas receptor (MasR). Whether increasing brain ACE2 activity reduces anxiety by stimulating central MasR is unknown. To test the hypothesis that increasing brain ACE2 activity reduces anxiety-like behavior via central MasR stimulation, we generated male mice overexpressing ACE2 (ACE2 KI mice) and wild type littermate controls (WT). ACE2 KI mice explored the open arms of the elevated plus maze (EPM) significantly more than WT, suggesting increasing ACE2 activity is anxiolytic. Central delivery of diminazene aceturate, an ACE2 activator, to C57BL/6 mice also reduced anxiety-like behavior in the EPM, but centrally administering ACE2 KI mice A-779, a MasR antagonist, abolished their anxiolytic phenotype, suggesting that ACE2 reduces anxiety-like behavior by activating central MasR. To identify the brain circuits mediating these effects, we measured Fos, a marker of neuronal activation, subsequent to EPM exposure and found that ACE2 KI mice had decreased Fos in the bed nucleus of stria terminalis but had increased Fos in the basolateral amygdala (BLA). Within the BLA, we determined that ∼62% of GABAergic neurons contained MasR mRNA and expression of MasR mRNA was upregulated by ACE2 overexpression, suggesting that ACE2 may influence GABA neurotransmission within the BLA via MasR activation. Indeed, ACE2 overexpression was associated with increased frequency of spontaneous inhibitory postsynaptic currents (indicative of presynaptic release of GABA) onto BLA pyramidal neurons and central infusion of A-779 eliminated this effect. Collectively, these results suggest that ACE2 may reduce anxiety-like behavior by activating central MasR that facilitate GABA release onto pyramidal neurons within the BLA.
authors.affiliation: Department of Pharmacodynamics, College of Pharmacy, University of Florida, 32611, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Physiology and Functional Genomics, College of Medicine, University of Florida, 32611, USA.
authors.forename: Annette D
authors.initials: AD
authors.lastname: de Kloet
authors.affiliation: Department of Pharmacodynamics, College of Pharmacy, University of Florida, 32611, USA.
authors.forename: Dipanwita
authors.initials: D
authors.lastname: Pati
authors.affiliation: Department of Pharmacodynamics, College of Pharmacy, University of Florida, 32611, USA.
authors.forename: Helmut
authors.initials: H
authors.lastname: Hiller
authors.affiliation: Department of Pharmacodynamics, College of Pharmacy, University of Florida, 32611, USA.
authors.forename: Justin A
authors.initials: JA
authors.lastname: Smith
authors.affiliation: Department of Physiology and Functional Genomics, College of Medicine, University of Florida, 32611, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Pioquinto
authors.affiliation: Department of Physiology and Functional Genomics, College of Medicine, University of Florida, 32611, USA.
authors.forename: Jacob A
authors.initials: JA
authors.lastname: Ludin
authors.affiliation: Department of Physiology and Functional Genomics, College of Medicine, University of Florida, 32611, USA.
authors.forename: S Paul
authors.initials: SP
authors.lastname: Oh
authors.affiliation: Department of Pharmacodynamics, College of Pharmacy, University of Florida, 32611, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Katovich
authors.affiliation: Department of Pharmacodynamics, College of Pharmacy, University of Florida, 32611, USA.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Frazier
authors.affiliation: Department of Physiology and Functional Genomics, College of Medicine, University of Florida, 32611, USA.
authors.forename: Mohan K
authors.initials: MK
authors.lastname: Raizada
authors.affiliation: Department of Pharmacodynamics, College of Pharmacy, University of Florida, 32611, USA. Electronic address: ekrause@cop.ufl.edu.
authors.forename: Eric G
authors.initials: EG
authors.lastname: Krause
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage / Q000031:analogs & derivatives; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001007:Anxiety / Q000201:enzymology*; D066272:Basolateral Nuclear Complex / Q000187:drug effects / Q000201:enzymology*; D053444:Inhibitory Postsynaptic Potentials; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D010446:Peptide Fragments / Q000008:administration & dosage; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012686:Septal Nuclei / Q000187:drug effects / Q000201:enzymology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: C092006:7-Ala-angiotensin (1-7); D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D000804:Angiotensin II; D005680:gamma-Aminobutyric Acid; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2
keywords: ACE2; Anxiety; Basolateral amygdala; GABA; Mas receptor; Stress