The dopaminergic system in neurodevelopment: preclinical models of neurodevelopmental disorders and susceptibility to neurodegeneration

Michele Santoni¹Andrea Mastio²Marco Pistis²Claudia Sagheddu^2*

• ¹University of Cagliari, Cagliari, Italy
• ²Universita degli Studi di Cagliari, Cagliari, Italy

The dopaminergic system plays a pivotal role in neurodevelopment, guiding the formation and refinement of neural circuits underlying salience attribution, cognition, reward and aversion. Its maturation extends from prenatal life through adolescence and may be influenced by genetic and environmental factors. Evidence from preclinical models suggests that perturbations during these sensitive windows may alter neurodevelopmental trajectories toward maladaptive outcomes, increasing vulnerability to neurodevelopmental disorders. This mini-review synthesizes findings from animal models to examine how physiological dopaminergic maturation might be shaped by genetic, as well as environmental, factors. We discussed maternal immune activation, prenatal cannabis exposure, and genetic models directly targeting dopaminergic function, all of which underscore the critical role of dopamine dysregulation in shaping neurodevelopmental outcomes. Beyond neurodevelopmental disorders, we extend this framework to newly emerging evidence concerning how early-life dopaminergic perturbations may influence dopamine system resilience and predispose individuals to accelerated cognitive decline and neurodegenerative disorders. Midbrain dopamine neurons exhibit intrinsic vulnerabilities that may render them especially sensitive to cumulative developmental and aging-related stressors and may serve as early predictors of disease. Finally, we discuss the therapeutic implications, emphasizing the limited mechanistic innovation in current pharmacological treatments and the growing need to target upstream or convergent developmental mechanisms in order to modify disease trajectories before overt dopaminergic dysfunction becomes established.