DP427 DEFICIENCY AND ITS IMPACT ON THUNDER SOUND-INDUCED FREEZING RESPONSES IN DUCHENNE MUSCULAR DYSTROPHY DOGS

Abstract Background Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease characterized by progressive muscle wasting caused by a mutation in the DMD gene which encodes dystrophin protein. Approximately 30% of DMD patients show cognitive deficits and psychiatric symptoms. In the brain, Dp427 dystrophin isoform is localized to a subset of GABAergic synapses in the amygdala and hippocampus. We previously reported that the number of GABAA receptor α2 clusters was reduced in the basolateral amygdala (BLA) of dystrophic mdx mice. This resulted in impaired GABAergic transmission in the BLA and a freezing response to threat. However, the characterization of brain Dp427 deficiency and its impact on brain phenotypes still need to be better understood. Canine X-linked muscular dystrophy in Japan (CXMDJ), a middle-sized and emotionally expressive model of DMD, is suitable for examining the neurobehavior associated with brain Dp427 deficiency. Aims & Objectives We aim to elucidate the molecular mechanism of brain Dp427 and the impact of its absence on brain phenotypes in CXMDJ. Method CXMDJ and wild-type littermates were observed in the thunder sound-induced fear response behavior. In this study, we used the open field apparatus consisting of an aluminum canine circle (W240 × L240 × H120 cm). Dogs were placed in a carrier cage, and the test was started when the door was opened. A reward was placed on the diagonal, and a thunder sound (110-140 dB) was presented when the dog approached the reward. A video camera was mounted on the ceiling to record each dog's behavior. Images were analyzed using image analysis software (Move-tr/2D). An electrocardiogram (ECG) measurement was recorded during the sound-induced fear response behavior to evaluate the emotional state. Results CXMDJ exhibited enhanced anxiety-like behavior in the open field test. The measurement of heart rate variability revealed decreased parasympathetic nerve activity in CXMDJ during the open field test. Moreover, CXMDJ showed an increased freezing behavior and decreased total distance traveled in the sound-induced fear response compared to wild-type littermates. This result suggests that CXMDJ exhibits enhanced fear behavior associated with brain Dp427 deficiency. Discussion & Conclusion We showed that CXMDJ exhibited highly anxiety-like behavior and freezing response. It is postulated that the absence of Dp427 in the amygdala may contribute to heightened anxiety and fear levels in CXMDJ.