MECP2 Deficiency Linked to Low Acetylcholine, Increased Symptoms
Female rats genetically engineered to carry a deficient Mecp2 gene — whose mutations are the leading cause of Rett syndrome — show social, behavioral, and motor symptoms that are similar to those of humans with the neurodevelopmental disorder, a study reports.
These symptoms were associated with low levels of the chemical messenger acetylcholine in the brain.
According to the scientists, this new animal model could be useful in studying the mechanisms underlining Rett syndrome — and for developing new treatments.
The study, “Substantial acetylcholine reduction in multiple brain regions of Mecp2-deficient female rats and associated behavioral abnormalities,” was published in the journal PLOS One.
Rett syndrome almost exclusively affects girls, beginning between 6-18 months of age, and leads to slowed growth, loss of motor control, and impaired learning, communication, and socialization.
The MECP2 gene contains the instructions for a protein with the same name, which is highly abundant in mature brain cells and regulates the expression, or activity, of other genes. More than 300 alterations in MECP2 have been documented in Rett and other mental health disorders.
Generally, to date, mouse models have been used to study the mechanisms of Rett syndrome, since they’re amenable to genetic manipulation. However, their small brain size limits the understanding of brain-specific alterations that occur in humans. Also, mouse models often do not recapitulate — or repeat in the animals — the most complex behavioral aspects of Rett.
To overcome some of these constraints, the researchers developed a new rat model of Rett — with these animals chosen because they’re more complex than mice. The new model was designed to allow scientists to better investigate the effects of a lack of functional Mecp2 (the rodent form of the human gene) on brain development, cognition, and behavior.
In this study, a team in Japan investigated the alterations in spatial learning and memory, brain tissue, and levels of neurotransmitters (chemical messengers) in a female rat model of Rett, genetically engineered to carry only one copy of the Mecp2 gene.
Compared with controls that had two Mecp2 copies, the Rett group showed a gradual decline with age on social interactions, which included genital investigation, sniffing, and social grooming. Specifically, the researchers found a significant decline in the frequency and duration of contact behaviors by week 23 of age, in contrast with the age-related increase observed in the control group. Also at this age, the Rett group rats exhibited a decline in both frequency and duration of self-grooming.
Spontaneous motor activity, monitored over two consecutive days, was lower in the Rett animals (ages 16 or 23 weeks, or about four to six months) compared with controls, both during the day but also at night, when rats tend to be more active.
Their motor coordination also was impaired at 26 weeks or six months of age, the team found. The Rett rats fell off an accelerating rotarod — essentially a spinning wheel with accelerating speed — at a lower rotation time and with less speed than did controls.
The researchers then assessed how a defective Mecp2 gene impaired the animals’ spatial learning — a key parameter for recognition of their environment and how to navigate it — and memory. For this purpose, they used the Morris water maze test, in which the animals are placed in a large circular pool of water and have to find a hidden platform. On test day, the platform is taken away and scientists evaluate whether the animals have memorized its former location.
The results confirmed that the Rett group had worse spatial learning and memory, as shown by increased escape latency, meaning they took longer to find the platform. Also, the swimming distance was longer and their frequency in crossing the platform’s location on test day was reduced compared with controls.
Brain tissue analysis revealed that, in the Rett group, the levels of the neurotransmitter acetylcholine were markedly reduced across several brain regions, including the hippocampus, an area important for learning and memory. Other affected brain regions included the amygdala, the caudate nucleus, and medulla oblongata.
Also, the number of astrocytes ━ a type of brain cell that supports the proper function of neurons ━ was reduced in areas such as the hippocampus and the brain’s frontal cortex in Rett females. The frontal cortex is the area responsible for controlling cognitive behavior, decision-making abilities, and moderating social behavior.
The blood levels of insulin-like growth factor 1 in Rett females, an important factor for the maintenance of neurons, also were markedly reduced when compared with controls.
Overall, these findings show that female rats deficient for the Mecp2 gene have several of the same disease attributes seen in Rett patients, supporting their use as a potential “robust model for future research on [Rett] pathobiology [processes] and treatment,” the team concluded.
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