• 22q11.2DS
• schizophrenia
• behaviour
• microglia
• neuroinflammation

Genetic risk factors have been consistently associated to the pathogenesis of different neurodevelopmental disorders.
22q11.2 deletion syndrome (22q.11.2DS, also known as DiGeorge Syndrome)is one of the most common copy number variants (CMVs) related to neurodevelopmental disorders such as attention-deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASD) and schizophrenia. Other than this higher vulnerability to neurodevelopmental disorders, the 22q11.2DS is characterized by immune abnormalities, including hypoplastic thymus, reduced T cells and increased vulnerability to infections. Nevertheless, whether there are immunological changes at the brain level is unknown. Studies on connections between the immune system and psychiatric disorders demonstrate that there is a certain level of communication between the immune state of the brain and the circulating immune cells. Moreover, this association seems to have effects also on behavioural developmental trajectories. However, how specific genetic alterations lead to an imbalance in the immunological homeostasis of the brain and consequently dysfunctional behaviours is still unclear. To better investigate this, here I used the heterozygote LgDel/+ mouse, that recapitulate the 22q11.2 genetic microdeletion and have been reported to present behavioural and morphological similarities to the equivalent human condition.
Moreover, I asked if it might be possible to rescue the 22q11.2DS phenotypes with an early intervention before the establishment of its altered tracts.
At the behavioral level, I sawthat LgDel/+ show Prepulse inhibition (PPI) deficits through their lifespan and social alterations starting from adolescence. However, these mice do not show impaired acoustic startle reactivity or basal levels of activity. Furthermore, mild motor coordination and balance impairments were evident only before adolescence.
At the immune system level, by flourescence-activated cell sorting (FACS) analyses, I found that LgDel/+ mice show a higher number of infiltrated leukocytes and peripheral monocytes-derived macrophages (mo-mφ) in the brain parenchyma compared to wild-type littermates (WT), indicating a persistent inflammatory state. In addition, mRNA expression profiling of FACS-isolated microglia revealed an increased proinflammatory state. Interestingly, I observed lower level of Oxytocin (OXT) at the level of the paravanticural nucleus (PVN), associated with lower levels of Oxytocin receptor (OXTr) in cortical microglia in LgDel/+ mice. This might suggest using OXT supplementation as possible ameliorative intervention in 22q11.2DS.
I am currently studying the effects of OXT treatment on LgDel/+ mice and control WT mice both at the behavioural and brain immunological level. Overall, these findings might elucidate the interconnection between genetic and immune system factors in the development of aberrant behaviours and how this could be used to bring out more effective intervention strategies.