Enhanced Glial Reaction and Altered Neuronal Nitric Oxide Synthase are Implicated in Attention Deficit Hyperactivity Disorder

Abstract

Attention deficit hyperactivity disorder (ADHD) has a complex etiology, and its specific causal factors remain to be elucidated. Aberration of nitric oxide synthase (nNOS) and inflammation, together with astrocytic and microglial cells have been continually associated with several neurological disorders, including ADHD. Using spontaneously hypertensive rat (SHR), we investigated the changes in nNOS, inflammatory, microglial and astrocytic markers in the frontal cortex and hippocampus at three different ages: onset of hypertension stage (i.e., 6 weeks after birth of SHR), established hypertension stage (i.e., 12 weeks after birth of SHR) and senescent stage (i.e., 12 months after birth of SHR), and compared with its age-matched normotensive control, Wistar-Kyoto (WKY) rats. A significant upregulation of Iba-1 expression in the senescent stage of SHR was observed. Further, we observed an upregulated nNOS expression in both onset and established stages of SHR, and a downregulated nNOS in the senescent stage. Our study showed an age-related increment of astrogliosis in the cortex and hippocampi of aged SHR. On the basis of our results, alterations in the nNOS and Iba-1 expressions, as well as age-related astrogliosis, may contribute to ADHD pathogenesis.

P2X4 signalling contributes to hyperactivity but not pain sensitization comorbidity in a mouse model of attention deficit/hyperactivity disorder

“…Microglia activation was previously described in the spontaneously hypertensive rat ( Zhang et al, 2022 ), and the 6-OHDA mouse ( Meseguer-Beltrán et al, 2023 ) models of ADHD. We decided to verify microglia reactivity in our conditions, and to investigate the consequences of P2X4 deletion on microglia changes.…”

“…Moreover, a genome-wide associated study identified causal genes for ADHD in microglia ( Fahira et al, 2019 ). Accordingly, microglia reactivity in ADHD conditions has been already demonstrated in humans ( Yokokura et al, 2021 ) and animal models ( Song et al, 2021 ; Zhang et al, 2022 ; Sanches et al, 2023 ). Recent evidence for microglia reactivity has been also provided in the ACC of the 6-OHDA mouse model ( Meseguer-Beltrán et al, 2023 ).…”

“…However, it has been suggested that inconsistent neurotransmission in neural circuits that engage the prefrontal cortex may account for fluctuations in attentional processing and cognitive performance and hence, for intra-individual variability ( Russell et al, 2006 ). Neurotransmission impairments can be caused by alterations in neurotransmitter release or binding ( Posner et al, 2020 ), neuroglia interactions ( Oades et al, 2010 ; Zhang et al, 2022 ), or neuroinflammatory processes ( Leffa et al, 2018 ; Corona, 2020 ).…”

Gut Metabolites Acting on the Gut-Brain Axis: Regulating the Functional State of Microglia

“…Immuno-fluorescence staining was used to detect the activation of CA1 in the hippocampus and microglia in the prefrontal cortex. Compared with normal rats, the expression of CA1 in the hippocampus and microglia in the prefrontal cortex of the SHRs was significantly increased [ 182 ]. This suggests that microglia may be involved in the pathogenesis of ADHD.…”

Is S100B Involved in Attention-Deficit/Hyperactivity Disorder (ADHD)? Comparisons with Controls and Changes Following a Triple Therapy Containing Methylphenidate, Melatonin and ω-3 PUFAs

“…The mechanisms leading to the catecholaminergic disruption observed in this disorder are multifactorial [ 16 ] and yet to be clarified. Increased glial activity has been reported in murine models of ADHD [ 17 , 18 ], suggesting involvement of glial cells in the functional and structural changes preceding ADHD symptoms. The glial function is essential for neuronal pruning and firing [ 6 , 19 ], network connectivity during development, and the secretion of pro-inflammatory and anti-inflammatory cytokines [ 20 ].…”