Relationships linking emotional, motor, cognitive and GABAergic dysfunctions in dystrophin-deficient mdx mice

Abstract

Alterations in the Duchenne muscular dystrophy (DMD) gene have been associated with enhanced stress reactivity in vertebrate species, suggesting a role for brain dystrophin in fear-related behavioral and cognitive processes. Because the loss of dystrophin (Dp427) reduces clustering of central γ-aminobutyric acid (GABAA) receptors, it is suspected that local inhibitory tuning and modulation of neuronal excitability are perturbed in a distributed brain circuit that normally controls such critical behavioral functions. In this study, we undertook a large-scale behavioral study to evaluate fear-related behavioral disturbances in dystrophin-deficient mdx mice. We first characterized the behavioral determinants of the enhanced fearfulness displayed by mdx mice following mild acute stress and its association with increased anxiety and altered fear memories. We further demonstrated that this enhanced fearfulness induces long-lasting motor inhibition, suggesting that neurobehavioral dysfunctions significantly influence motor outcome measures in this model. We also found that mdx mice are more sensitive to the sedative and hypnotic effects of 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol hydrochlorid (THIP), a selective pharmacological activator of extrasynaptic GABAA receptors involved in central tonic inhibition. Our results highlight that information on the emotional aspects of mdx mice are important to better understand the bases of intellectual and neuropsychiatric defects in DMD and to better define valuable functional readouts for preclinical studies. Our data also support the hypothesis that altered spatial localization of GABAA receptors due to Dp427 loss is a pathological mechanism associated with brain dysfunction in DMD, suggesting that extrasynaptic GABAA receptors might be candidate targets for future therapeutic developments.

Cognitive impairment appears progressive in the mdx mouse

“…In this present study male mdx mice were group houses (average 4 males per cage) and exposed to the same maze for 5 consecutive days, and yet a proportion of mdx mice still exhibit complete lasting tonic immobility (freezing response) at 12 months old during the Barnes maze test. This phenotype could be used to potentially assess the dynamics of therapeutic agents targeting brain dysfunctions in this model of DMD, as similarly suggested by Vaillend and Chaussenot [75] .…”

“…Furthermore, previous reports detail a potent freezing response in male mdx mice, expressed as lasting tonic immobility, reminiscent of the natural defensive deathfeigning posture that animals exhibit when confronted by a predator or other threat, which is theorised to involve a brain circuit that includes the amygdala [75] . Authors suggest that if mdx mice were group housed rather than singly housed, and exposed to a familiar environment, this response could be reduced.…”

Inspiratory pressure‐generating capacity is preserved during ventilatory and non‐ventilatory behaviours in young dystrophic mdx mice despite profound diaphragm muscle weakness

“…), GABAergic dysfunction (Sekiguchi et al . ; Vaillend & Chaussenot, ) and cognitive deficits (Chaussenot et al . ).…”

“…Dystrophin is ordinarily expressed in neurons (Lidov, 1996). In the mdx mouse model of DMD, studies indicate reduced number of corticospinal neurons (Sbriccoli et al 1995), damage to motor pathways (Carretta et al 2001), loss of neuronal projections (Pinto et al 2008), GABAergic dysfunction (Sekiguchi et al 2009;Vaillend & Chaussenot, 2017) and cognitive deficits (Chaussenot et al 2015). It is unclear whether dystrophin deficiency affects the nervous system control of breathing.…”

Mass spectrometry‐based protein analysis to unravel the tissue pathophysiology in Duchenne muscular dystrophy

“…However, unlike the manifestations of the disease in the skeletal and cardiac muscle the symptoms of the brain in DMD are not of a progressive nature. It has been demonstrated that the dystrophin‐deficient mdx mouse displays alterations in learning, behavior, fear response, and memory . Glial fibrillary acidic protein was upregulated in the mdx‐4cv brain in an unbiased proteomic investigation, which is of considerable interest as it is a well‐established indicator of brain damage further evidencing brain involvement in DMD .…”