Targeting brain receptor yields little benefit in Rett syndrome mice
Additional studies needed to evaluate HRH3 as potential treatment target
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Levels of the genetic instructions for a brain receptor protein were reduced in people with Rett syndrome and in a mouse model of the disease, but activating the receptor produced little to no benefit in mice, a U.S. study found.
Researchers found lower levels of messenger RNA (mRNA) for the histamine H3 receptor, or HRH3, across several brain regions in people with Rett and in female Mecp2Null/+ mice, a commonly used animal model of the disease. mRNA is the intermediate molecule that carries instructions from genes to make proteins.
However, treatment with (R)-alpha-methylhistamine (RAMH), an experimental compound that activates HRH3, had little to no beneficial effect on the Rett-related behaviors tested. The findings point to altered HRH3 signaling in Rett, but further studies are needed to understand the impact of reduced HRH3 mRNA levels and whether HRH3 could offer a potential treatment target.
The study, “Exploration of the therapeutic potential of the HRH3 histamine receptor in MECP2-related disorders,” was published in Neuropharmacology.
Earlier work found lower levels of HRH3 mRNA in brain region
In most cases, Rett is caused by mutations in the MECP2 gene that disrupt the production of MeCP2, a protein that normally helps regulate the activity of other genes, particularly in nerve cells. This impairs nerve cell communication and alters brain development, leading to Rett symptoms such as repetitive hand movements, cognitive issues, and behavioral problems such as anxiety.
Because MeCP2 regulates the activity of many genes, studying changes in gene activity in the brains of people with Rett may help identify biological mechanisms involved in the disease and potential treatment targets.
Previous work by the researchers pointed to HRH3 as one such target. HRH3 is a receptor found widely throughout the brain that helps regulate the release of histamine, a chemical messenger involved in brain signaling. It also influences the release of other chemical messengers involved in brain function.
In an analysis of donated brain tissue from people with Rett, the researchers found significantly lower levels of HRH3 mRNA in the temporal cortex, a brain region involved in memory and processing sensory information. Previous studies have also linked HRH3 to anxiety-like and obsessive-compulsive-like behaviors.
Together, these findings prompted the team of researchers in the U.S. to investigate HRH3 more closely in Rett and test whether targeting the receptor could ease Rett-related behaviors.
Treatment had no significant effect on overall movement
The researchers first confirmed lower HRH3 mRNA levels in the temporal cortex of donated brain tissue from people with Rett, and then extended those findings to other brain regions, including the motor cortex, which helps control voluntary movement, and the cerebellum, which helps coordinate movement. Together, the results supported HRH3 as a potential treatment target in Rett.
They then looked for similar changes in female Mecp2Null/+ mice. As in the human samples, HRH3 mRNA levels were significantly reduced in some brain regions compared with healthy mice. These included the cortex and striatum, a region involved in movement and behavior.
Having confirmed reduced HRH3 levels in the Rett mice, the researchers next tested whether activating the receptor could ease Rett-related behaviors.
Female Mecp2Null/+ mice experiencing symptoms were treated with RAMH, a compound that activates HRH3, or a control solution. The researchers then assessed behaviors related to movement, anxiety, repetitive behaviors, and learning and memory.
Our findings reveal that, despite significant decreases in histamine HRH3 mRNA [levels] in both humans and a mouse model of RTT [Rett], administration of the histamine HRH3 receptor agonist, RAMH, induced little to no beneficial impact on [disease features] in RTT model mice.
RAMH showed a potential benefit for anxiety-like behavior. In an elevated maze, treated Rett mice spent significantly more time in the open areas than untreated Rett mice, which is generally interpreted as indicating less anxiety. Other measures in the same test, however, were not significantly changed.
The treatment also failed to ease other Rett-related behaviors tested. RAMH did not reduce hindlimb clasping, an abnormal behavior in which mice pull their hind legs toward their body when suspended by the tail, or improve learning and memory. It also had no significant effect on overall movement.
“Our findings reveal that, despite significant decreases in histamine HRH3 mRNA [levels] in both humans and a mouse model of RTT [Rett], administration of the histamine HRH3 receptor agonist, RAMH, induced little to no beneficial impact on [disease features] in RTT model mice,” the researchers wrote.
The researchers cautioned that lower HRH3 mRNA does not necessarily mean there is less HRH3 receptor protein in specific areas of the brain. The receptor can also work differently depending on where it is located in brain cells and which signaling pathways it affects, making the consequences of altered HRH3 mRNA levels difficult to predict.
“Future studies would be needed to understand the impact of changes in HRH3 receptor expression,” the team concluded.
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