Neonatal meningitis induces ADHD-like behaviors via modulation of dopaminergic inputs by macrophages

Abstract Neonatal meningitis often causes neurodevelopmental disorders, including attention deficit hyperactivity disorder (ADHD), in adulthood. However, the molecular mechanism by which neonatal meningitis induces brain dysconnectivity, leading to neurodevelopmental disorders, remains unclear. To investigate the pathological mechanisms of neonatal meningitis-induced neurodevelopmental disorders, we established mouse model of neonatal meningitis by injecting carrageenan, and found that mice with neonatal meningitis exhibited ADHD-like behaviors later in life and neural hyperactivation in the nucleus accumbens due to the increase in dopaminergic inputs induced by macrophages. RNA-sequencing revealed macrophages in carrageenan-treated mice express increased level of Semaphorin 4A (Sema4A), and treatment with a Sema4A neutralizing antibody prevented ADHD-like behaviors after carrageenan treatment. In addition, Sema4A concentration was increased in the cerebrospinal fluid of patients with meningitis, and Sema4A promoted dopaminergic synapse formation in human neurons. Collectively, these findings suggest macrophages increase dopaminergic inputs by producing Sema4A, which is a critical factor in the development of neonatal meningitis-induced ADHD-like behaviors.