Role of pentraxin 3 in neurodevelopmental disorders

Control of synapse number and function is critical to the formation of neural circuits. We recently demonstrated that the innate immune molecule, pentraxin3 (PTX3), released by astrocytes, promotes the formation of functional excitatory synapses. PTX3 interacts with thrombospondin1 (TSP1), an astrocyte-derived factor which controls the formation of silent synapses. PTX3:TSP1 interaction exerts a negative regulation of PTX3 itself suggesting that the relative amount of these proteins and their complex are crucial to set the balance between synaptic growth and synapse maturation. Prenatal inflammation and maternal immune activation (MIA) are recognized risk factors for neurodevelopmental diseases. Preclinical studies established a causal link between MIA and the disruption of the proper neurodevelopmental trajectory in the offspring. Of note, PTX3 is stimulated by inflammatory insults and, as a consequence, PTX3 and TSP1 may change their levels upon immune challenge during brain development.

Starting from these premises, we aim to investigate how prenatal immune stimulation affects PTX3 and TSP1 levels and how this impacts synaptogenesis and brain circuit development.

Using a mouse model of MIA we demonstrated that prenatal inflammation disrupts the physiological developmental pattern of expression of PTX3 and alters the PTX3:TSP1 ratio in in the cerebral cortex during the postnatal period of synaptogenesis. Moreover, we observed morphological and functional alterations in astrocytes, which are the main source of PTX3. We are currently investigating the consequences at neuronal and synaptic level. Furthermore, we are investigating the involvement of PTX3 alteration in a human cohort of premature neonates (ELGAN study) characterized by enhanced frequency of autism spectrum disorders and the regulation of PTX3 inflammatory conditions in human iPSC-derived glial cells.