Altered sensitivity to pain starts early in life in Rett mice: Study
Impairment occurs before the onset of motor symptoms
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A lack of enough MecP2 protein, a hallmark of Rett syndrome, may impair sensitivity to pain before the onset of motor symptoms, a new study suggests.
The study used female mice with mutations in one of the Mecp2 gene copies (Mecp2-het), which leads to a deficiency of the MecP2 protein.
“Our data supports the validity of Mecp2-het females from the presymptomatic phase to study [Rett] and the importance of assessing symptom progression to get a full understanding of the consequences derived from … Mecp2 deficiencies,” researchers wrote.
The study, “Longitudinal analysis in Mecp2-het female mice reveals atypical nociceptive behaviours,” was published in the Journal of Molecular Medicine.
Significant variability in timing, progression of symptoms
Rett syndrome is chiefly caused by mutations in the MECP2 gene that result in low levels of functional MeCP2, a protein that regulates the activity of other genes and helps maintain the health of brain cells. This disrupts normal brain development and function, ultimately leading to disease symptoms.
Rett almost exclusively affects females. The MECP2 gene is located on the X chromosome. Females have two X chromosomes, and males have one X and one Y chromosome. Girls and women with Rett have one X chromosome with a mutant copy of MECP2, and the other with a healthy copy that can partially compensate for the mutation.
In this study, researchers in Ireland, Spain, and Portugal analyzed symptom progression in adult female Mecp2-het mice.
First, they found significant variability in the timing and progression of symptoms, particularly clasping, a marker of the onset of pronounced symptoms, which was assessed by holding mice by the tail for up to 15 seconds.
About 10% of the mice presented clasping at two months of age, whereas half did so at four months and almost all by six months. The age of four months was thereby defined as the threshold dividing the early symptomatic and the late symptomatic groups. No control (wild-type) mouse showed clasping behavior.
Sensitivity to mechanical stimuli decreased as disease progressed
Mecp2‑het mice showed increasing body weight as the disease progressed, although the trend was somewhat distinct between early-onset and late-onset disease. Regarding gait pattern, the front paws were affected in both groups, while the back paws were more affected in the early-symptomatic group.
Compared with healthy females, Mecp2-het females initially showed elevated sensitivity to mechanical stimuli, meaning their threshold of applied pressure to be perceived as pain was lower. But that sensitivity decreased as the disease progressed, with late-symptomatic mice showing results similar to controls at six months, and early-symptomatic animals actually showing lower sensitivity by four months.
Responses to temperature were measured using the hot plate test, which recorded the time the animals took to lick their paws in response to heat. Walking backwards, a behavior attributed by the scientists to the motor impairments caused by Rett, was also analyzed. Overall, results showed that Mecp2-het females were more sensitive to heat than healthy mice, but there were no differences between the early- and late-onset groups.
“Taken together, our data support that MeCP2 deficiency might cause heightened sensitivity to mechanical and thermal stimulation, albeit masked by the onset of motor symptoms,” the researchers wrote, noting that these findings “align with clinical observations in [Rett],” as the symptoms “typically [follow] a progressive course, with severity increasing over time.”
Further analysis demonstrated decreased activation of nerve cells in the periaqueductal grey of Rett mice in response to the hot plate stimulus. The periaqueductal grey is a brain region primarily responsible for modulating pain.
Taken together, our results reveal that pain might be largely hidden in mouse models of [Rett] and highlight the need of future studies to ameliorate pain conditions in [Rett] patients.
Additionally, these females showed a reduction in cannabinoid receptor 1 levels in this area compared to control mice at six months of age. Studies suggest that a lack of MeCP2 results in alterations in the endocannabinoid system, which is involved in pain processing. Similar results were observed for the number of nerve cells in the periaqueductal grey producing MeCP2, particularly in females with early-onset symptoms.
“Notably, pharmacological modulation of the endocannabinoid system has been explored as a therapeutic strategy in [Rett], with some clinical trials reporting a [70% to 75%] reduction in seizure frequency,” the researchers wrote. “Taken together, our results reveal that pain might be largely hidden in mouse models of [Rett] and highlight the need of future studies to ameliorate pain conditions in [Rett] patients.”
