Nomo1 deficiency causes autism-like behavior in zebrafish.

Patients with neuropsychiatric disorders often exhibit a combination of clinical symptoms such as autism, epilepsy, or schizophrenia, complicating diagnosis and development of therapeutic strategies. Functional studies of novel genes associated with co-morbidities can provide clues to understand the pathogenic mechanisms and interventions. NOMO1 is one of the candidate genes located at 16p13.11, a hotspot of neuropsychiatric diseases. Here, we generate nomo1-/- zebrafish to get further insight into the function of NOMO1. Nomo1 mutants show abnormal brain and neuronal development and activation of apoptosis and inflammation-related pathways in the brain. Adult Nomo1-deficient zebrafish exhibit multiple neuropsychiatric behaviors such as hyperactive locomotor activity, social deficits, and repetitive stereotypic behaviors. The Habenular nucleus and the pineal gland in the telencephalon are affected, and the melatonin level of nomo1-/- is reduced. Melatonin treatment restores locomotor activity, reduces repetitive stereotypic behaviors, and rescues the noninfectious brain inflammatory responses caused by nomo1 deficiency. These results suggest melatonin supplementation as a potential therapeutic regimen for neuropsychiatric disorders caused by NOMO1 deficiency.

Behavioural responses of zebrafish larvae to acute ethosuximide exposure.

The anticonvulsant drug ethosuximide has shown diverse anxiety-related activity in rodents, but research in zebrafish is limited. To evaluate the effects of acute ethosuximide exposure on locomotor activity and anxiety-related thigmotaxis behaviours of zebrafish larvae, the activity of AB strain zebrafish larvae at 5 and 7 days postfertilization (dpf) was analysed under normal constant illumination and stressful light-dark transitions. Under constant illumination, ethosuximide at concentrations of 2, 5 and 10 mmol/l increased the distances travelled and intensified locomotor responses to a novel environment. In addition, 40 mmol/l ethosuximide decreased the travel distance and attenuated the locomotor response to darkness. The effects were age related. Under constant illumination, ethosuximide at 40 mmol/l reduced thigmotaxis behaviours in larvae at both ages. Under the light-dark transition, 5 mmol/l ethosuximide reduced thigmotaxis behaviours in 7-dpf larvae. We concluded that under constant lighting, ethosuximide at low concentrations (2, 5 and 10 mmol/l) stimulated the locomotor activity of zebrafish larvae, whereas a high concentration (40 mmol/l) inhibited the activity. Ethosuximide at a low concentration (5 mmol/l) showed anxiolytic effects during the stressful light-dark transition in 7-dpf larvae. The effects of ethosuximide were age and concentration related.

Anxiety-related behavioral responses of pentylenetetrazole-treated zebrafish larvae to light-dark transitions.

Pentylenetetrazole (PTZ), γ-aminobutyrate (GABA) antagonist, is a convulsant drug, known to induce anxiety and seizures in zebrafish. Changes in the mobility of zebrafish under light-dark transitions reflect anxiety level, serving as a useful behavioral readout. The effects of PTZ treatment have yet to be assayed in this manner. Zebrafish larvae (AB strain) at both 5dpf (days post-fertilization) and 7dpf were treated with different concentrations of PTZ. General locomotor activity and thigmotaxis were analyzed under continuous illumination (normal conditions) or alternating light-dark cycles (stressful conditions). Zebrafish larvae of 5dpf and 7dpf exhibited different sensitivities to PTZ. Anxiety level, measured in terms of response to illumination transitions under the influence of PTZ, demonstrated contrasting tendencies. Dark-light transitions dramatically increased the locomotor activity of zebrafish larvae receiving 8mM PTZ which was indicative of anxiety. This study suggests that PTZ increases the susceptibility by activating the neuron, which perhaps makes light change easier to influence the anxiety level of larvae. We provide useful evidence for putative anti-anxiety drug screening.