Anti-inflammatory effects of dopamine on microglia and a D1 receptor agonist ameliorates neuroinflammation of the brain in a rat delirium model.

Microglia play a central role in neuroinflammatory processes by releasing proinflammatory mediators. This process is tightly regulated along with neuronal activities, and neurotransmitters may link neuronal activities to the microglia. In this study, we showed that primary cultured rat microglia express the dopamine (DA) D1 receptor (D1R) and D4R, but not D2R, D3R, or D5R. In response to a D1R-specific agonist SKF-81297 (SKF), the cultured microglia exhibited increased intracellular cAMP levels. DA and SKF suppressed lipopolysaccharide (LPS)-induced expression of interleukin-1ß (IL-1ß) and tumor necrosis α (TNFα) in cultured microglia. Microglia in the normal mature rat prefrontal cortex (PFC) were sorted and significant expression of D1R, D2R, and D4R was observed. A delirium model was established by administering LPS intraperitoneally to mature male Wistar rats. The model also displayed sleep-wake disturbances as revealed by electroencephalogram and electromyogram recordings as well as increased expression of IL-1ß and TNFα in the PFC. DA levels were increased in the PFC 21 h after LPS administration. Increased cytokine expression was observed in sorted microglia from the PFC of the delirium model; however, TNFα, but not IL-1ß expression, was abruptly decreased 21 h after LPS administration in the delirium model, whereas DA levels were increased. A D1R antagonist SCH23390 partially abolished the TNFα expression change. This suggests that endogenous DA may play a role in suppressing neuroinflammation. Administration of the DA precursor L-DOPA or SKF to the delirium model rats inhibited the expression of IL-1ß and TNFα. The simultaneous administration of clozapine, a D4R antagonist, strengthened the suppressive effects of L-DOPA. These results suggest that D1R mediates the suppressive effects of LPS-induced neuroinflammation, in which microglia may play an important role. Agonists for D1R may be effective for treating delirium.

Rearing in an Enriched Environment Ameliorates the ADHD-like Behaviors of Lister Hooded Rats While Suppressing Neuronal Activities in the Medial Prefrontal Cortex.

In addition to genetic factors, environmental factors play a role in the pathogenesis of attention deficit/hyperactivity disorder (ADHD). This study used Lister hooded rats (LHRs) as ADHD model animals to evaluate the effects of environmental factors. Male LHR pups were kept in four rearing conditions from postnatal day 23 (4 rats in a standard cage; 12 rats in a large flat cage; and 4 or 12 rats in an enriched environment [EE]) until 9 weeks of age. EE rearing but not rearing in a large flat cage decreased the activity of LHRs in the open field test that was conducted for 7 consecutive days. In the drop test, most rats reared in an EE remained on a disk at a height, whereas most rats reared in a standard cage fell off. RNA sequencing revealed that the immediate-early gene expression in the medial prefrontal cortex of LHRs reared in an EE was reduced. cFos-expressing neurons were reduced in number in LHRs reared in an EE. These results suggest that growing in an EE improves ADHD-like behaviors and that said improvement is due to the suppression of neuronal activity in the mPFC.

Length impairments of the axon initial segment in rodent models of attention-deficit hyperactivity disorder and autism spectrum disorder.

The axon initial segment (AIS) is a structural neuronal compartment of the proximal axon that plays key roles in sodium channel clustering, action potential initiation, and signal propagation of neuronal outputs. Mutations in constitutive genes of the AIS, such as ANK3, have been identified in patients with neurodevelopmental disorders. Nevertheless, morphological changes in the AIS in neurodevelopmental disorders have not been characterized. In this study, we investigated the length of the AIS in rodent models of attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). We observed abnormalities in AIS length in both animal models. In ADHD model rodents, we observed shorter AIS length in layer 2/3 (L2/3) neurons of the medial prefrontal cortex (mPFC) and primary somatosensory barrel field (S1BF). Further, we observed shorter AIS length in S1BF L5 neurons. In ASD model mice, we observed shorter AIS length in L2/3 and L5 neurons of the S1BF. These results suggest that impairments in AIS length are common phenomena in neurodevelopmental disorders such as ADHD and ASD and may be conserved across species. Our findings provide novel insight into the potential contribution of the AIS to the pathophysiology and pathogenesis of neurodevelopmental disorders.