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Reciprocal social interactions in a novel cage. a Male–female interactions expressed by the number of orofacial, orogenital, and body contacts initiated by WT and mdx resident mice towards control intruder females. b–d Male–male interactions expressed by the behavioral responses initiated by WT (white bars) and mdx resident male mice (black bars) during interactions with WT and mdx male intruders (intruder’s genotype indicated on the X-axis). Histograms show the number of contacts (b), dominant acts (c), and pursuits (d) performed by resident test mice. e–g Behaviors initiated by WT and mdx intruder male mice during interactions with WT and mdx male residents. Histograms show the number of contacts (e), dominant acts (f), and pursuits (g) performed by the intruders. *p < 0.05
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The Duchenne and Becker muscular dystrophies (DMD, BMD) show significant comorbid diagnosis for autism, and the genomic sequences encoding the proteins responsible for these diseases, the dystrophin and associated proteins, have been proposed as new candidate risk loci for autism. Dystrophin is expressed not only in muscles but also in central inhi...
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... social behavior of mdx resident males differed de- pending on the sex and genotype of the intruder. As shown in Fig. 3a, mdx mice initiated fewer contacts with females as compared to WT mice (p < 0.005; Fig. 3a), which was not associated with changes in specific types of contacts. In male-male encounters ( Fig. 3b-d), the mdx resident mice also displayed fewer contacts towards mdx male intruders (p < 0.05) but conversely initiated more contacts than ...
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... social behavior of mdx resident males differed de- pending on the sex and genotype of the intruder. As shown in Fig. 3a, mdx mice initiated fewer contacts with females as compared to WT mice (p < 0.005; Fig. 3a), which was not associated with changes in specific types of contacts. In male-male encounters ( Fig. 3b-d), the mdx resident mice also displayed fewer contacts towards mdx male intruders (p < 0.05) but conversely initiated more contacts than control residents when confronted to WT intruders (p < 0.05) (Fig. 3b). In any cases, no fights ...
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... social behavior of mdx resident males differed de- pending on the sex and genotype of the intruder. As shown in Fig. 3a, mdx mice initiated fewer contacts with females as compared to WT mice (p < 0.005; Fig. 3a), which was not associated with changes in specific types of contacts. In male-male encounters ( Fig. 3b-d), the mdx resident mice also displayed fewer contacts towards mdx male intruders (p < 0.05) but conversely initiated more contacts than control residents when confronted to WT intruders (p < 0.05) (Fig. 3b). In any cases, no fights were observed and the latency of the first contact (all <10 s) and the number of dominant acts initiated ...
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... as compared to WT mice (p < 0.005; Fig. 3a), which was not associated with changes in specific types of contacts. In male-male encounters ( Fig. 3b-d), the mdx resident mice also displayed fewer contacts towards mdx male intruders (p < 0.05) but conversely initiated more contacts than control residents when confronted to WT intruders (p < 0.05) (Fig. 3b). In any cases, no fights were observed and the latency of the first contact (all <10 s) and the number of dominant acts initiated by resident test mice (Fig. 3c) were comparable regardless of the intruder's genotype (p > 0.05). However, the in- creased number of contacts with WT intruders, as shown in Fig. 3b, was associated with the ...
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... resident mice also displayed fewer contacts towards mdx male intruders (p < 0.05) but conversely initiated more contacts than control residents when confronted to WT intruders (p < 0.05) (Fig. 3b). In any cases, no fights were observed and the latency of the first contact (all <10 s) and the number of dominant acts initiated by resident test mice (Fig. 3c) were comparable regardless of the intruder's genotype (p > 0.05). However, the in- creased number of contacts with WT intruders, as shown in Fig. 3b, was associated with the initiation of an increased number of pursuits directed against the WT intruders (p < 0.05). This was not observed when mdx residents were confronted with mdx ...
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... to WT intruders (p < 0.05) (Fig. 3b). In any cases, no fights were observed and the latency of the first contact (all <10 s) and the number of dominant acts initiated by resident test mice (Fig. 3c) were comparable regardless of the intruder's genotype (p > 0.05). However, the in- creased number of contacts with WT intruders, as shown in Fig. 3b, was associated with the initiation of an increased number of pursuits directed against the WT intruders (p < 0.05). This was not observed when mdx residents were confronted with mdx intruders (p > 0.05; Fig. 3d), showing that pursuit behavior, as well as the number of contacts, varied depending on the intruder's ...
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... comparable regardless of the intruder's genotype (p > 0.05). However, the in- creased number of contacts with WT intruders, as shown in Fig. 3b, was associated with the initiation of an increased number of pursuits directed against the WT intruders (p < 0.05). This was not observed when mdx residents were confronted with mdx intruders (p > 0.05; Fig. 3d), showing that pursuit behavior, as well as the number of contacts, varied depending on the intruder's ...
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... the intruder's behavior also varied de- pending on the resident's genotype (Fig. 3e-g). The be- havior of mdx intruders was not influenced by the resident's genotype while, in contrast, the behavior of WT intruders varied when confronted with mdx resi- dents: indeed, the WT intruders initiated more contacts (Fig. 3e), dominant acts (Fig. 3f ), and pursuits (Fig. 3g) during interactions with mdx residents than with other ...
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... the intruder's behavior also varied de- pending on the resident's genotype (Fig. 3e-g). The be- havior of mdx intruders was not influenced by the resident's genotype while, in contrast, the behavior of WT intruders varied when confronted with mdx resi- dents: indeed, the WT intruders initiated more contacts (Fig. 3e), dominant acts (Fig. 3f ), and pursuits (Fig. 3g) during interactions with mdx residents than with other WT residents (all parameters, p < 0.05). This suggests that mdx mice, when acting as passive (or receptive) res- idents, were showing more submissive responses com- pared to ...
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... the intruder's behavior also varied de- pending on the resident's genotype (Fig. 3e-g). The be- havior of mdx intruders was not influenced by the resident's genotype while, in contrast, the behavior of WT intruders varied when confronted with mdx resi- dents: indeed, the WT intruders initiated more contacts (Fig. 3e), dominant acts (Fig. 3f ), and pursuits (Fig. 3g) during interactions with mdx residents than with other WT residents (all parameters, p < 0.05). This suggests that mdx mice, when acting as passive (or receptive) res- idents, were showing more submissive responses com- pared to ...
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... behavior also varied de- pending on the resident's genotype (Fig. 3e-g). The be- havior of mdx intruders was not influenced by the resident's genotype while, in contrast, the behavior of WT intruders varied when confronted with mdx resi- dents: indeed, the WT intruders initiated more contacts (Fig. 3e), dominant acts (Fig. 3f ), and pursuits (Fig. 3g) during interactions with mdx residents than with other WT residents (all parameters, p < 0.05). This suggests that mdx mice, when acting as passive (or receptive) res- idents, were showing more submissive responses com- pared to ...
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Background:
Duchenne muscular dystrophy is a fatal cardiac and skeletal muscle disease resulting from mutations in the dystrophin gene. We have previously demonstrated that a dystrophin-associated protein, sarcospan (SSPN), ameliorated Duchenne muscular dystrophy skeletal muscle degeneration by activating compensatory pathways that regulate muscle...
Duchenne muscular dystrophy (DMD), caused by mutations in the gene encoding for the cytoskeletal protein dystrophin, is linked with severe cardiac complications including cardiomyopathy development and cardiac arrhythmias. We and others recently reported that currents through L-type calcium (Ca) channels were significantly increased, and channel in...
Delivery of miniaturized dystrophin genes via adeno-associated viral vectors is one leading approach in development to treat Duchenne muscular dystrophy. Here we directly compared the functionality of five mini- and micro-dystrophins via skeletal muscle-specific transgenic expression in dystrophin-deficient mdx mice. We evaluated their ability to r...
Duchenne muscular dystrophy is caused by mutations in the DMD gene that disrupt the open reading frame and prevent the full translation of its protein product, dystrophin. Restoration of the open reading frame and dystrophin production can be achieved by exon skipping using antisense oligonucleotides targeted to splicing elements. This approach aim...
Muscle regeneration depends on satellite cells, quiescent precursors that, in consequence of injury or in pathological states such as muscular dystrophies, activate, proliferate, and differentiate to repair the damaged tissue. A subset of satellite cells undergoes self-renewal, thus preserving the satellite cell pool and its regenerative potential....
Citations
... Mdx mice, which have a point mutation in exon 23 and consequently lack Dp427, have been most thoroughly studied. They show impaired functioning in cognitive processes concerning social behavior, 21 spatial and recognition memory, 22 depressive-like behavior 23 and anxiety and fear. [24][25][26] Only recently, the consequences of the additional lack of Dp140 have been investigated in the mdx52 mouse, which have a deletion of exon 52, and mdx 4cv mice, which have a nonsense mutation in exon 53. ...
Duchenne muscular dystrophy is a severe neuromuscular disorder that is caused by mutations in the DMD gene, resulting in a disruption of dystrophin production. Next to dystrophin expression in the muscle, different isoforms of the protein are also expressed in the brain and lack of these isoforms leads to cognitive and behavioral deficits in patients. It remains unclear how the loss of the shorter dystrophin isoform Dp140 affects these processes. Using a variety of behavioral tests, we found that mdx and mdx4cv mice (which lack Dp427 or Dp427 + Dp140, respectively) exhibit similar deficits in working memory, movement patterns and blood–brain barrier integrity. Neither model showed deficits in spatial learning and memory, learning flexibility, anxiety or spontaneous behavior, nor did we observe differences in aquaporin 4 and glial fibrillary acidic protein. These results indicate that in contrast to Dp427, Dp140 does not play a crucial role in processes of learning, memory and spontaneous behavior.
... Sociability measurements were performed in a clear acrylic three-chamber cage (60 × 42 × 20 cm each) [76,77]. The middle chamber was used as a resting point, and the chambers on the side hold two small cylindrical cages that contained an unfamiliar mouse or a neutral small object [78,79]. Unfamiliar male mice were habituated to remain into the cylinder cages 2 days prior testing. ...
Astrocytes play crucial roles in brain homeostasis and are regulatory elements of neuronal and synaptic physiology. Astrocytic alterations have been found in Major Depressive Disorder (MDD) patients; however, the consequences of astrocyte Ca²⁺ signaling in MDD are poorly understood. Here, we found that corticosterone-treated juvenile mice (Cort-mice) showed altered astrocytic Ca²⁺ dynamics in mPFC both in resting conditions and during social interactions, in line with altered mice behavior. Additionally, Cort-mice displayed reduced serotonin (5-HT)-mediated Ca²⁺ signaling in mPFC astrocytes, and aberrant 5-HT-driven synaptic plasticity in layer 2/3 mPFC neurons. Downregulation of astrocyte Ca²⁺ signaling in naïve animals mimicked the synaptic deficits found in Cort-mice. Remarkably, boosting astrocyte Ca²⁺ signaling with Gq-DREADDS restored to the control levels mood and cognitive abilities in Cort-mice. This study highlights the important role of astrocyte Ca²⁺ signaling for homeostatic control of brain circuits and behavior, but also reveals its potential therapeutic value for depressive-like states.
... Sociability measurements were performed in a clear acrylic three-chamber cage (60 x 42 x 20 cm each) 107,108 . The middle chamber was used as a resting point, and the chambers on the side hold two small cylindrical cages that contained an unfamiliar mouse or a neutral small object 109,110 . Unfamiliar male mice were habituated to remain into the cylinder cages 2 days prior testing. ...
Astrocytes play crucial roles in brain homeostasis and are regulatory elements of neuronal and synaptic physiology. Astrocytic alterations have been found in Major Depressive Disorder (MDD) patients; however, the consequences of astrocyte Ca ²⁺ signaling in MDD are poorly understood. Here, we found that corticosterone-treated mice (Cort-mice) showed altered astrocytic Ca ²⁺ dynamics in mPFC both in resting conditions and during social interactions, in line with altered mice behavior. Additionally, Cort-mice displayed reduced serotonin (5-HT)-mediated Ca ²⁺ signaling in mPFC astrocytes, and aberrant 5-HT-driven synaptic plasticity in layer 2/3 mPFC neurons. Downregulation of astrocyte Ca ²⁺ signaling in naïve animals mimicked the synaptic deficits found in Cort-mice. Remarkably, boosting astrocyte Ca ²⁺ signaling with Gq-DREADDS restored mood and cognitive deficits in Cort-mice to control levels. This study highlights the important role of astrocyte Ca ²⁺ signaling for homeostatic control of brain circuits and behavior, but also reveals its potential therapeutic value for depressive-like states.
... For example, the gene Autism susceptibility candidate 2 (AUTS2), which experienced intensified selection in social spiders, regulates neuronal and synaptic development and influences social behaviors in mice 56 and mutation in AUTS2 has been associated with multiple neurological diseases, including autism in humans 57,58 . The gene dystrophin, isoforms A/C/F/G/H (Dys), which experienced intensified selection in social spiders, affects social behavior, communication, and synaptic plasticity in mice 59,60 , and mutations in Dys are associated with autism and intellectual disability in humans 60 . The gene Synaptogenesis protein syg-2 (syg-2), which experienced relaxed selection in social spiders, determines synapse formation, and mutations in syg-2 are associated with locomotor behaviors in worms 61,62 . ...
The transition from solitary to social life is a major phenotypic innovation, but its genetic underpinnings are largely unknown. To identify genomic changes associated with this transition, we compare the genomes of 22 spider species representing eight recent and independent origins of sociality. Hundreds of genes tend to experience shifts in selection during the repeated transition to social life. These genes are associated with several key functions, such as neurogenesis, behavior, and metabolism, and include genes that previously have been implicated in animal social behavior and human behavioral disorders. In addition, social species have elevated genome-wide rates of molecular evolution associated with relaxed selection caused by reduced effective population size. Altogether, our study provides unprecedented insights into the genomic signatures of social evolution and the specific genetic changes that repeatedly underpin the evolution of sociality. Our study also highlights the heretofore unappreciated potential of transcriptomics using ethanol-preserved specimens for comparative genomics and phylotranscriptomics.
... Previous studies showed that a selective disruption of Dp427 expression in humans may affect specific types of memory and executive functions, as well as verbal skills and social and emotional behaviors (Cyrulnik and Hinton, 2008;Hinton et al., 2000Hinton et al., , 2006Ricotti et al., 2016b;Wicksell et al., 2004). This is also supported by preclinical studies in the Dp427-deficient mdx mouse model of DMD that displays memory deficits as well as emotional and social disturbances, which have been associated with altered synaptic plasticity in various brain structures (Miranda et al., 2015;Sekiguchi et al., 2009;Vaillend et al., 1995Vaillend et al., , 2004Vaillend and Chaussenot, 2017). Studies of mouse models and cell lines with selective or additional loss of Dp140 and Dp71 also support the hypothesis that distal mutations may affect distinct brain functions, including glial functions, and contribute to variations in phenotype severity (Chaussenot et al., 2019;Daoud et al., 2008;Lange et al., 2022;Saoudi et al., 2021). ...
Duchenne muscular dystrophy (DMD) is caused by X-linked inherited or de novo DMD gene mutations predominantly affecting males who develop early-onset muscle degeneration, severely affecting their quality of life and leading to reduced life expectancy. DMD patients may also develop proliferative retinopathy, cataract, ERG abnormalities, altered contrast sensitivity, color vision losses, and elevated flash detection thresholds during dark adaptation. Depending on the position of the genetic alteration in the large DMD gene, it is associated with a lack of the full-length dystrophin protein possibly with an additional loss of one or several other dystrophins, which are normally transcribed from internal promoters in retina and crystalline lens. During the last decades, the properties of the dystrophins have been characterized in patients with different genetic alterations and in genetic mouse models of DMD. The complex expression pattern of the dystrophins in photoreceptors, Müller glial cells and astrocytes, likely influences synaptic transmission, ionic balance and vascular integrity of the retina. However, the specific function of each retinal dystrophin remains largely unknown. This review describes the current knowledge on dystrophin expression, the putative molecular, structural, and physiological properties of retinal dystrophins, and the main clinical implications associated with the loss of dystrophins in DMD patients and mouse models. Current data and working hypotheses warrant future research on retinal dystrophins to increase our understanding of dystrophin function in the central nervous system in general and to unveil new retinal mechanisms and therapeutic avenues for retinal diseases.
... A reduction in syllable repertoire has also been described in genetic NDD models, such as Cd157 KO mice (Lopatina et al., 2017) and Tbx1 heterozygous mice (Hiramoto et al., 2011;Takahashi et al., 2016). In addition, we observed an altered composition of syllables in the AFO group, which has previously been reported in other models, such as the Reelin mutant (Romano et al., 2013), fmr1 knockout (Lai et al., 2014), ScSn-Dmd mdx /J mutant (Miranda et al., 2015), and Tbx1 heterozygous (Hiramoto et al., 2011;Takahashi et al., 2016) mice. Thus, our model of advanced paternal age showing impairments in syllable properties and composition also fits the NDD-like phenotype. ...
Infant crying is a communicative behavior impaired in neurodevelopmental disorders (NDDs). Because advanced paternal age is a risk factor for NDDs, we performed computational approaches to evaluate how paternal age affected vocal communication and body weight development in C57BL/6 mouse offspring from young and aged fathers. Analyses of ultrasonic vocalization (USV) consisting of syllables showed that advanced paternal age reduced the number and duration of syllables, altered the syllable composition, and caused lower body weight gain in pups. Pups born to young fathers had convergent vocal characteristics with a rich repertoire, whereas those born to aged fathers exhibited more divergent vocal patterns with limited repertoire. Additional analyses revealed that some pups from aged fathers displayed atypical USV trajectories. Thus, our study indicates that advanced paternal age has a significant effect on offspring’s vocal development. Our computational analyses are effective in characterizing altered individual diversity.
... To clarify the hypothesis that lack of Dp140 impacts the neurobehavioural comorbidities of mice, we thus evaluated social interaction (Makinodan et al., 2012;Yizhar et al., 2011) in 8-week-old mdx52 mice and vocal communication in mdx52 pups on a postnatal day 7. Compared to wild-type (WT) and mdx23 mice, mdx52 mice exhibited a longer interaction time with a stranger mouse (Fig. 1A). To evaluate genetic and neural mechanisms underpinning social communication (Berg et al., 2018;Miranda et al., 2015), we examined ultrasonic vocalizations in pups to assess mother-pup interactions. Consistent with social interaction test results in adult mdx52 mice, mdx52 pups displayed more frequent and longer isolation calls during mother-pup separation when compared to WT and mdx23 pups (Fig. 1B). ...
Duchenne muscular dystrophy (DMD) is a muscle disorder caused by DMD mutations and is characterized by neurobehavioural comorbidities due to dystrophin deficiency in the brain. The lack of Dp140, a dystrophin short isoform, is clinically associated with intellectual disability and autism spectrum disorders (ASDs), but its postnatal functional role is not well understood. To investigate synaptic function in the presence or absence of brain Dp140, we utilized two DMD mouse models, mdx23 and mdx52 mice, in which Dp140 is preserved or lacking, respectively. ASD-like behaviours were observed in pups and 8-week-old mdx52 mice lacking Dp140. Paired-pulse ratio of excitatory postsynaptic currents, glutamatergic vesicle number in basolateral amygdala neurons, and glutamatergic transmission in medial prefrontal cortex-basolateral amygdala projections were significantly reduced in mdx52 mice compared to those in wild-type and mdx23 mice. ASD-like behaviour and electrophysiological findings in mdx52 mice were ameliorated by restoration of Dp140 following intra-cerebroventricular injection of antisense oligonucleotide drug-induced exon 53 skipping or intra-basolateral amygdala administration of Dp140 mRNA-based drug. Our results implicate Dp140 in ASD-like behaviour via altered glutamatergic transmission in the basolateral amygdala of mdx52 mice.
... Lack of dystrophin in mdx mice is responsible for several behavioral and neurophysiological alterations, such as reduced sensitivity to nicotine-induced enhanced memory (Coccurello et al., 2002), impaired long-term spatial and recognition memory, and enhanced CA1 hippocampal long-term potentiation (Vaillend et al., 2004), impairment of both acquisition and long-term retention of cued and trace fear memories, and reduced path efficiency in the Morris water maze spatial learning . In addition, mdx mice are characterized by alterations associated to posttraumatic disorders, such as altered social behavior and ultrasonic communication, which are traits typical of autism spectrum disorders (Miranda et al., 2015), increased anxiety and altered fear memories (Vaillend and Chaussenot, 2017;Comim et al., 2019), deficits on the habituation, aversive, and object recognition memory, and depression-like behavior (Comim et al., 2019). However, behavioral and neurological manifestations in mdx mice are milder than in DMD patients and in mdx 3cv mice, a mdx mouse variant, which carries a point mutation within intron 65 of the Dmd gene and lacks the expression of all short dystrophin isoforms (Im et al., 1996;Willmann et al., 2009). ...
Dystrophinopaties, e.g., Duchenne muscular dystrophy (DMD), Becker muscular dystrophy and X-linked dilated cardiomyopathy are inherited neuromuscular diseases, characterized by progressive muscular degeneration, which however associate with a significant impact on general system physiology. The more severe is the pathology and its diversified manifestations, the heavier are its effects on organs, systems, and tissues other than muscles (skeletal, cardiac and smooth muscles). All dystrophinopaties are characterized by mutations in a single gene located on the X chromosome encoding dystrophin (Dp427) and its shorter isoforms, but DMD is the most devasting: muscular degenerations manifests within the first 4 years of life, progressively affecting motility and other muscular functions, and leads to a fatal outcome between the 20s and 40s. To date, after years of studies on both DMD patients and animal models of the disease, it has been clearly demonstrated that a significant percentage of DMD patients are also afflicted by cognitive, neurological, and autonomic disorders, of varying degree of severity. The anatomical correlates underlying neural functional damages are established during embryonic development and the early stages of postnatal life, when brain circuits, sensory and motor connections are still maturing. The impact of the absence of Dp427 on the development, differentiation, and consolidation of specific cerebral circuits (hippocampus, cerebellum, prefrontal cortex, amygdala) is significant, and amplified by the frequent lack of one or more of its lower molecular mass isoforms. The most relevant aspect, which characterizes DMD-associated neurological disorders, is based on morpho-functional alterations of selective synaptic connections within the affected brain areas. This pathological feature correlates neurological conditions of DMD to other severe neurological disorders, such as schizophrenia, epilepsy and autistic spectrum disorders, among others. This review discusses the organization and the role of the dystrophin-dystroglycan complex in muscles and neurons, focusing on the neurological aspect of DMD and on the most relevant morphological and functional synaptic alterations, in both central and autonomic nervous systems, described in the pathology and its animal models.
... One of the features that we would like to suggest deepening for future research is represented by social cognitions. Considering that some patients exhibit ASD in comorbidity and that altered social behavior has also been highlighted on animal models with dystrophin mutations and in DMD patients (Hinton et al., 2007;Miranda et al., 2015), it may be useful to verify these aspects, especially in toddlers. An early intervention on these problems can help psychic development and prevention of psychiatric disorders. ...
Background
Brain co-morbidities in DMD are well-documented, less is known about the cognitive, behavioral and psychosocial functioning of patients with BMD.
Methods
The systematic review was carried out on two databases (Pubmed and Scopus) according to the PRISMA guidelines. We included all research articles specific to BMD written after 1995.
Results
Studies examining neuropsychological and neurobehavioral functioning in BMD are few and have several methods limitations. BMD population is characterized by high rates of cognitive impairment, with specific involvement of different cognitive areas. Unlike DMD, verbal skills are better preserved. Neurodevelopmental and emotional/behavioral disorders have great importance in BMD, due to their high prevalence. Lack of Dp140 or Dp71 can cause intellectual disability, these isoforms are probably responsible for the other brain-related comorbidities as well.
Discussion
The results suggest that cognitive and neuropsychiatric comorbid symptoms may affect a significant proportion of BMD patients therefore it is important to mental health and neuropsychological screening. Finding tools for an adequate assessment is a priority in order to include brain outcome measures in clinical trials.
... A mouse model of DMD, the mdx mouse, lacks full-length Dp427 but retains shorter isoforms due to a nonsense mutation in exon 23 of the Dmd gene. 14 The CNS phenotype of the mdx mouse includes impairments in long-term spatial and recognition memory, learning, cognitive flexibility and social communication, [15][16][17][18] as well as increased fearfulness and stress reactivity, such as enhanced defensive 'freezing' startle responses during mild behavioural stress 19 or foot shock. 20 Recent work comparing the mdx mouse with a mouse model lacking both Dp427 and Dp140 (mdx52) found no differences in startle responses between the mdx and mdx52 mice, although mdx52 mice showed increased anxiety behaviours. ...
Duchenne muscular dystrophy is characterised by loss of dystrophin in muscle, however patients also have variable degree of intellectual disability and neurobehavioural co-morbidities. In contrast to muscle, in which a single full-length dystrophin isoform (Dp427) is produced, multiple isoforms are produced in the brain, and their deficiency accounts for the variability of CNS manifestations, with increased risk of comorbidities in patients carrying mutations affecting the 3’ end of gene, which disrupt expression of shorter Dp140 and Dp71 isoforms. A mouse model (mdx mouse) lacks Dp427 in muscle and CNS and exhibits exaggerated startle responses to threat, linked to the deficiency of dystrophin in limbic structures such as the amygdala, which normalise with postnatal brain dystrophin-restoration therapies. A pathological startle response is not a recognised feature of DMD, and its characterisation has implications for improved clinical management and translational research.
To investigate startle responses in Duchenne muscular dystrophy, we used a novel fear-conditioning task in an observational study of 56 males aged 7-12 years (31 affected boys, mean age 9.7 ± 1.8 years; 25 controls, mean age 9.6 ± 1.4 years). Trials of two neutral visual stimuli were presented to participants: one ‘safe’ cue presented alone; one ‘threat’ cue paired with an aversive noise to enable conditioning of physiological startle responses (skin conductance response and heart rate). Retention of conditioned physiological responses was subsequently tested by presenting both cues without the aversive noise in an ‘Extinction’ phase. Primary outcomes were the initial unconditioned skin conductance and change in heart rate responses to the aversive ‘threat’ and acquisition and retention of conditioned responses after conditioning. Secondary and exploratory outcomes were neuropsychological measures and genotype associations.
The mean unconditioned skin conductance response was greater in the Duchenne group than Controls (mean difference 3.0µS (1.0, 5.1); P = .004), associated with a significant threat-induced bradycardia only in the patient group (mean difference -8.7bpm (-16.9, -0.51); P = .04). Duchenne participants found the task more aversive than Controls, with increased early termination rates during the Extinction phase (26% in Duchenne group vs. 0% Controls; P = .007).
This study provides the first evidence that boys with Duchenne muscular dystrophy show similar increased unconditioned startle responses to threat to the mdx mouse, which in the mouse respond to brain dystrophin restoration. Our study provides new insights into the neurobiology underlying the complex neuropsychiatric co-morbidities in Duchenne muscular dystrophy and defines an objective measure of this CNS phenotype, which will be valuable for future CNS-targeted dystrophin-restoration studies.
