Lack of neuronal nitric oxide synthase results in attention deficit hyperactivity disorder-like behaviors in mice.

Abstract

Nitric oxide (NO) is an important molecule for the proper development and function of the central nervous system. In this study, we investigated the behavioral alterations in the neuronal nitric oxide synthase knockout mice (NOS1 KO) with a deficient NO production mechanism in the brain, characterizing it as a potential rodent model for attention deficit / hyperactivity disorder (ADHD). NOS1 KO exhibited higher locomotor activity than their wildtype counterparts in a novel environment, as measured by open field (OF) test. In a two-way active avoidance paradigm (TWAA), we found sex-dependent effects, where male KO displayed deficits in avoidance and escape behavior, sustained higher incidences of shuttle crossings and higher incidences of inter-trial interval crossings, suggesting learning and/or performance impairments. On the other hand, female KO demonstrated few deficits in TWAA. Molsidomine (MSD), a NO donor, rescued TWAA deficits in male KO when acutely administered before training. In a passive avoidance paradigm, KO of both sexes displayed significantly shorter step-through latencies after training. Further, abnormal spontaneous motor activity rhythms were found in the KO during the dark phase of the day, indicating dysregulation of rhythmic activities. These data indicate that NOS1 KO mimic certain ADHD-like behaviors and could potentially serve as a novel rodent model for ADHD.

Neuronal Nitric Oxide Synthase

“…Attention deficit/hyperactivity disorder (ADHD) is a psychiatric disorder with inattention, hyperactivity and impulsivity as main signs, and is frequently associated with learning disability, substance abuse, epilepsy and other psychiatric disorders such as anxiety and disruption of circadian rhythm [55]. In other study, they reported that NOS1 Ex1f-VNTR is involved in impulsive and empathic personality traits and associated with self-rated impulsiveness and venturesomeness [56].…”

“…Moreover, past findings showed that NOS1 knockout mice (NOS1 KO) could be a candidate model for ADHD. Behaviourally, NOS1 KO is apparently hyperactive and exhibits abnormal social, aggressive and impulsive behaviours as well as deficits in learning and memory [55].…”

Imaging genetics in neurodevelopmental psychopathology

“…In exon 1f, a functional VNTR that affects gene expression has been linked to hyperactive and impulsive behavior in humans (Reif et al, 2009;Weber et al, 2015), with the short allele being the risk factor for ADHD. In addition, a recent Nos1 knock-out mouse model showed dysregulation of rhythmic activities mimicking ADHD-like behaviors (Gao & Heldt, 2015).…”

Neuronal Nitric Oxide Synthase Knockdown Within Basolateral Amygdala Induces Autistic-Related Phenotypes and Decreases Excitatory Synaptic Transmission in Mice

“…It was shown that nNOS deficiency impairs long-term memory of olfactory fear learning ( Pavesi et al, 2013 ). nNOS knockout mice are reportedly hyperactive and display abnormal social, aggressive, and impulsive behaviors as well as cognitive impairments ( Gao and Heldt, 2015 ). Noticeably, we have recently reported that downregulated nNOS of the BLA is a neuropathological finding in the VPA-treated mice ( Wang et al, 2017 , 2018a ).…”