Low microglial activity correlates with hyperactivity in attention deficit/hyperactivity disorder model rats: A study using an adrenergic β2 agonist as a microglia activator

Microglial cells have been said to play a significant role in the pathogenesis of neurodevelopmental disorders. Lister hooded rats (LHRs), an outbred strain, have been reported to exhibit hyperactive, impulsive, and inattentive behaviors and have served as attention deficit/hyperactivity disorder (ADHD) model animals. Notably, compared to eight-week-old male Wistar rats, the expression of microglial markers and phagocytosis-related factors was lower in the medial prefrontal cortex (mPFC) of male LHRs of the same age. The blood-brain barrier-permeable adrenergic β2 agonist clenbuterol (CLB) suppresses lipopolysaccharide (LPS)-induced proinflammatory activation in cultured rat primary microglia. However, in the absence of LPS, CLB increased CD11b expression in cultured cells, whereas noradrenaline decreased it. When CLB was subcutaneously administered to LHRs, microglial cell size and CD11b and CD68 protein expression were increased in the frontal cortex. CLB also elevated the expression of the mRNA encoding CD68, C1qb, and macrophage-expressed gene 1 (mpeg1), which are likely responsible for microglial synaptic elimination. CLB also decreased the mRNA expression for immediate early genes and vesicular glutamate transporter 1. CLB administration decreased the hyperactivity of LHRs but did not affect their inattentive behavior. Microglia sorted from the PFC of CLB-administered LHRs contained more synapsin 1 and a glutamatergic synapse protein PSD95 than those sorted from vehicle-administered LHRs. Immunoblotting of PFC tissues revealed that the amounts of cFos and PSD95 were higher in LHRs than in Wistar rats. CLB administration decreased the expression of both proteins. These results suggest that microglia may be responsible for the regulation of motor activity by eliminating excitatory synapses and that the adrenergic β2 receptor may activate microglial phagocytic action. • This study demonstrated low microglial activity in Lister hooded rats, an ADHD model. • An adrenergic β2 receptor agonist clenbuterol (CLB) increased microglial activity. • CLB enhanced phagocytic elimination of excitatory synapses by microglia. • CLB decreased hyperactivity of the animals but did not affect inattentive behavior. • Microglia may regulate the magnitude of motor activity by eliminating synapses.