NOX1/NADPH Oxidase Promotes Synaptic Facilitation Induced by Repeated D₂Receptor Stimulation: Involvement in Behavioral Repetition

Abstract

Repetitive behavior is a widely observed neuropsychiatric symptom. Abnormal dopaminergic signaling in the striatum is one of the factors associated with behavioral repetition; however, the molecular mechanisms underlying the induction of repetitive behavior remain unclear. Here, we demonstrated that the NOX1 isoform of the superoxide-producing enzyme NADPH oxidase regulated repetitive behavior in mice by facilitating excitatory synaptic inputs in the central striatum (CS). In male C57Bl/6J mice, repeated stimulation of D 2 receptors induced abnormal behavioral repetition and perseverative behavior. Nox1 deficiency or acute pharmacological inhibition of NOX1 significantly shortened repeated D 2 receptor stimulation-induced repetitive behavior without affecting motor responses to a single D 2 receptor stimulation. Among brain regions, Nox1 showed enriched expression in the striatum, and repeated dopamine D 2 receptor stimulation further increased Nox1 expression levels in the CS, but not in the dorsal striatum. Electrophysiological analyses revealed that repeated D 2 receptor stimulation facilitated excitatory inputs in the CS indirect pathway medium spiny neurons (iMSNs), and this effect was suppressed by the genetic deletion or pharmacological inhibition of NOX1. Nox1 deficiency potentiated protein tyrosine phosphatase activity and attenuated the accumulation of activated Src kinase, which is required for the synaptic potentiation in CS iMSNs. Inhibition of NOX1 or b-arrestin in the CS was sufficient to ameliorate repetitive behavior. Striatal-specific Nox1 knockdown also ameliorated repetitive and perseverative behavior. Collectively, these results indicate that NOX1 acts as an enhancer of synaptic facilitation in CS iMSNs and plays a key role in the molecular link between abnormal dopamine signaling and behavioral repetition and perseveration.

Amelioration of obsessive-compulsive disorder by intracellular acidification of cortical neurons with a proton pump inhibitor

“…a decrease in the binding availability of striatal D 2 R [ 11 ]) have been reported in patients with primary OCD, there may be pathological similarities between patients with primary OCD and medication-induced OCD-like symptoms, especially dopaminergic abnormalities. Consistent with this postulation, we found that repeated administration of a D 2 R agonist (quinpirole; QNP) induced OCD-like repetitive and perseverative behaviours in mice [ 12 , 13 ]. This finding demonstrates a common therapeutic strategy for primary OCD and medication-induced OCD-like symptoms.…”

“…Repeated injections of a D 2 R agonist (QNP) elicit OCD-like behavioural and neurological abnormalities in mice [ 12 , 13 , 17 ]. We assessed the effects of PPIs on QNP-induced OCD-like behaviours to obtain preclinical proof-of-concept.…”

“…We assessed the effects of PPIs on QNP-induced OCD-like behaviours to obtain preclinical proof-of-concept. We previously showed that repeated injection of QNP induced repetitive behaviour [ 12 , 13 , 17 ]. Consistent with our previous observations, repeated intraperitoneal injection of QNP (1 mg/kg/day, eight times) significantly induced excessive repetition of spontaneous chewing behaviour (Fig.…”

“…The mice were singly housed; subsequently, spontaneous behaviour in their home cage was recorded starting from 20 min after the last drug injection for 10 min, when chewing was most strongly induced, as previously defined [ 12 , 13 ]. Chewing was defined as holding a wood chip in the forelimbs and biting and pulling it with the mouth and forelimbs.…”

“…As previously described [ 13 ], each brain region of 1-mm coronal brain slices was removed based on the Brain Atlas [ 19 ].…”