Reduced MeCP2 signaling leads to hypoalgesia in a mouse model of Rett syndrome

Mutations in methyl-CpG binding protein (MeCP2) cause Rett syndrome

Rett syndrome is a rare, X-linked dominant neurological disorder that occurs almost exclusively in females. The disease, which typically is diagnosed in girls by 18 months of age, is characterized by respiratory abnormalities, multiple motor deficits, absence of speech, increased gastrointestinal disorders, seizure activity, and decreased sensitivity to painful stimuli (hypoalgesia). This neurodevelopmental disorder, historically mis-diagnosed as cerebral palsy or autism, results from mutations in methyl-CpG binding protein (MeCP2). In March 2016 a team led by Dr. Koichi Iwata from the Nihon University School of Dentistry in Tokyo, Japan reported their findings on the role of MeCP2 signaling in tongue heat sensitivity in a mouse model of Rett syndrome (Suzuki et al. 2016). Their data advances our understanding of MeCP2’s role in modulating pain and for the hypoalgesia associated with the disease.

MeCP2 signaling regulates transient receptor vanilloid 1 (TRPV1) in pain modulation

MeCP2 is expressed predominately in mature neurons.  Historically, MeCP2 has been characterized as a transcriptional repressor by modulating gene expression through histone deacetylation, but recent reports suggest that MeCP2 may activate transcription also. Mutations in MeCP2 that inactivate the protein - single DNA base pair changes, insertions, deletions, or mutations that affect RNA splicing - produce the Rett syndrome phenotypes, including hypoalgesia.  Earlier studies showed that MeCP2 levels are increased in dorsal ganglion neurons following peripheral nerve injury that produce an increased sensitivity to pain, or hyperalgesia. Together, these observations implicate decreased MeCP2 expression in the hypoalgesia that occurs in Rett syndrome patients.

TRPV1 in nociceptive primary afferent neurons is activated in part by harmful heat stimuli, and plays an important role in pain modulation. Research shows that TRPV1 expression increases in trigeminal ganglion (TG) neurons and in primary afferent terminals near the inflammation induction site in an animal model for facial inflammation. Understanding how MeCP2 is involved in in regulating TRPV1 expression in TG and primary neurons could shed some light on the molecular basis that underlies the hypoalgesia experienced by Rett syndrome patients.

A mouse model of Rhett syndrome supports the importance of MeCP2 in hypoalgesia

To model Rett syndrome facial hypoalgesia, Dr. Iwata's group administered submucosal injections of Complete Freund's Adjuvant (CFA) into the tongue of B6.129P2(C)-Mecp2tm1.1Bird/J (Stock# 003890) heterozygote (Mecp2+/-) and wild-type females. To assess heat sensitivity and inflammatory pain, a graded heat stimulus (35-60°C, 1°C/s) was applied to the tongue, and the lowest temperature that evoked a head withdrawal, defined as heat head-withdrawal reflex threshold (HHWT), was recorded. CFA induced long-lasting and robust heat sensitivity in wild-type mice, but not in Mecp2+/- mice. In fact, Mecp2+/- mice injected with saline or CFA showed less heat sensitivity than wild-type mice injected with saline, indicating that the Mecp2+/- mice experienced hypoalgesia. Although TRPV1 was expressed in MeCP2-positive TG neurons innervating the tongue in both wild-type and Mecp2+/- mice, a significantly smaller number of TRPV1-positive neurons were observed in the tongues of heterozygotes compared to wild-types. Together, these data suggest that the hypoalgesia observed in this mouse model is induced by the inhibition of TRPV1 expression, and this expression is dependent in part on MeCP2 signaling.

Recent reports suggest that MeCP2 not only represses downstream gene transcription via histone deacetylation, but also can activate it. In this study, Dr. Iwata's group showed that following CFA injections into the tongues of wild-type females, the number of MeCP2 and TRPV1-immunoreactive (IR) neurons and MeCP2 protein expression were significantly increased in TG neurons innervating the tongue. Additionally, TG neurons innervating the tongue also expressed acetyl-histone H3. In Mecp2+/- mice, the number of MeCP2-IR and TRPV1-IR TG neurons did not increase after CFA injection, nor was there an increase in TG neurons that expressed acetyl-histone H3. This suggests that MeCP2-dependent H3 deacetylation enhances TRPV1 expression in TG neurons, which leads to inflammatory pain in the tongue following CFA administration.

These findings suggest that tongue heat sensitivity and inflammatory hyperalgesia are dependent on TRPV1 expression in TG neurons that innervate the tongue and that this expression is regulated by MeCP2 signaling, supporting a role for MeCP2 in pain modulation. Hypoalgesia is a potentially dangerous condition that may result in more severe tissue damage from burns or other physical trauma due to a blunted pain withdrawal reflex.  Understanding how MeCP2 modulates pain might lead to therapies that improve the pain sensitivity in Rett syndrome patients, as well as treatments that might help to reduce neuropathic pain associated with other genetic or acquired conditions.