Reduced Firing of Nucleus Accumbens Parvalbumin Interneurons Impairs Risk Avoidance in DISC1 Transgenic Mice

A strong animal survival instinct is to approach objects and situations that are of benefit and to avoid risk. In humans, a large proportion of mental disorders are accompanied by impairments in risk avoidance. One of the most important genes involved in mental disorders is disrupted-in-schizophrenia-1 (DISC1), and animal models in which this gene has some level of dysfunction show emotion-related impairments. However, it is not known whether DISC1 mouse models have an impairment in avoiding potential risks. In the present study, we used DISC1-N terminal truncation (DISC1-N-TM) mice to investigate risk avoidance and found that these mice were impaired in risk avoidance on the elevated plus maze (EPM) and showed reduced social preference in a three-chamber social interaction test. Following EPM tests, c-Fos expression levels indicated that the nucleus accumbens (NAc) was associated with risk-avoidance behavior in DISC1-N-TM mice. In addition, in vivo electrophysiological recordings following tamoxifen administration showed that the firing rates of fast-spiking neurons (FS) in the NAc were significantly lower in DISC1-N-TM mice than in wild-type (WT) mice. In addition, in vitro patch clamp recording revealed that the frequency of action potentials stimulated by current injection was lower in parvalbumin (PV) neurons in the NAc of DISC1-N-TM mice than in WT controls. The impairment of risk avoidance in DISC1-N-TM mice was rescued using optogenetic tools that activated NAcPV neurons. Finally, inhibition of the activity of NAcPV neurons in PV-Cre mice mimicked the risk-avoidance impairment found in DISC1-N-TM mice during tests on the elevated zero maze. Taken together, our findings confirm an impairment in risk avoidance in DISC1-N-TM mice and suggest that reduced excitability of NAcPV neurons is responsible.

Automated summary

Research showed that DISC1-N-TM mice exhibited impaired risk avoidance, with reduced activity of fast-spiking neurons and lower action potential frequency in parvalbumin neurons in the nucleus accumbens compared to wild-type mice. Activation of NAcPV neurons using optogenetic tools rescued the impairment in risk avoidance in DISC1-N-TM mice. Inhibition of NAcPV neuron activity in PV-Cre mice mimicked the risk-avoidance impairment seen in DISC1-N-TM mice.