Mental disorders, such as Attention deficit hyperactivity disorder (ADHD), and 22q11 deletion syndrome (22q11DS) are both related to a dopaminergic system dysfunction. Several studies have shown that dopamine (DA) not only mediates interactions into the nervous system, but can also contribute to the modulation of immunity via receptors expressed in the immune cells (Nagakome et al., 2011; Nakano et al., 2011). Autoimmunity in the central nervous system has been suggested to play a pivotal role in the pathogenesis of neurodevelopmental disorders (ND) (Schwartz. 2013), but how an immune system alteration might lead to ADHD and participate to the psychiatric features of the 22q11DS is still unclear. The importance of immune system for life-long maintenance of the brain is demonstrated by its role in the formation of new neurons, support to normal cognitive performance and neurogenesis regulation. These evidences have broken the theory of the central nervous system (CNS) as immune privileged organ, indicating that peripheral immune cells can contribute to brain homeostasis and repair. In particular, it was demonstrated that circulating blood macrophages recruitment in brain parenchyma is needed for CNS health and homeostasis. The immune cells access to the CNS is regulated by choroid plexus (CP) activation, promoted by pro-inflammatory signals from both brain parenchyma or peripheral T cells accumulated in CP (Baruch et al., 2015).
Importantly, a possible role of the neuropeptide adrenomedullin (ADM) in ND has been suggested, since several studies reported a role of this peptide as a biomarker of different psychiatric disorders, such as Alzheimer (Fernandez et al., 2016), autism (Zoroglu et al., 2003), bipolar disorder (Akpinar et al., 2013), schizophrenia (Chia-Hsing Huang et al., 2004) and ADHD (Fernandez et al., 2008). ADM is a regulatory peptide involved in thymic immune tolerance mechanisms (Rulle et al., 2012; Castellani et al., 2016), which are suggested to be altered in ND.
On the basis of these considerations, in this study we investigated the involvement of immunological mechanisms and their dependence to ADM both in the periphery and in CNS in mouse models of ADHD and 22q11DS, in order to define whether an immunomodulatory approach can be useful in the management of these diseases.