Citation

Frau R, Fanni S, Serra V, Simola N, Godar S, Traccis F, Devoto P, Bortolato M, Melis M. Neuropharmacology 2019; ePub(ePub): ePub.

Affiliation

Division of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, 09042, Monserrato, Italy; National Institute of Neuroscience (INN), Italy. Electronic address: myriam@unica.it.

Copyright

(Copyright © 2019, Elsevier Publishing)

DOI

10.1016/j.neuropharm.2019.01.032

PMID

30738037

Abstract

Aggressive behavior (AB) is a multifaceted disorder based on the interaction between genetic and environmental factors whose underlying mechanisms remain elusive. The best-characterized gene by environment (GxE) interaction for AB is the relationship between child neglect/abuse and low-activity alleles of the monoamine-oxidase A (MAOA) gene. MAOA oxidizes monoamines like serotonin and dopamine, whose aberrant signaling at discrete developmental ages plays a pivotal role in the ontogeny of AB. Here, we investigated the impact of this GxE on dopamine function at pre-adolescence by exposing hypomorphic MAOA (MAO^Neo) mice to early life stress (ES) and by performing behavioral and ex vivo electrophysiological analyses in the ventral tegmental area (VTA) and the prefrontal cortex (PFC). MAOA^Neo ES mouse dopamine neurons exhibited an enhanced post-synaptic responsiveness to excitatory inputs, aberrant plasticity in the PFC, and an AB. Systemic administration of the selective antagonist at dopamine D1 receptors SCH23390 fully restored PFC function and rescued AB. Collectively, these findings reveal that dysfunctional mesocortical dopamine signaling at pre-adolescence ties to AB in the MAOA^Neo ES mouse, and identify dopamine D1 receptor as a molecular target to be exploited for an age-tailored therapy.

Copyright © 2019. Published by Elsevier Ltd.

Language: en

Keywords

Aggression; Dopamine; MAOA; Prefrontal cortex; Ventral tegmental area