Brain Adenosine System May Be Therapeutic Target in Rett, Mouse Study Reports
The study, “Impairment of adenosinergic system in Rett syndrome: Novel therapeutic target to boost BDNF signalling,” was published in the journal Neurobiology of Disease.
Most cases of Rett are caused by mutations in the MECP2 gene, which codes for a protein called MeCP2 that regulates the activity of other genes.
One such gene encodes a protein known as brain-derived neurotrophic factor (BDNF), which plays an essential role in nerve cell development and maturation.
Studies have shown that BDNF levels are decreased in mouse models of Rett. The overproduction of BDNF in studies led to eased symptoms, suggesting that this protein is part of the Rett disease mechanism. In fact, analyses in brain tissue collected post-mortem found that the RNA levels of BDNF, which serve as template for protein production, were decreased in people with Rett.
However, therapies designed to deliver BDNF to the brain are limited by the blood-brain barrier — a selective membrane that regulates which molecules enter the brain. As such, small molecules that can cross the blood-brain barrier may be able to boost BDNF’s effects.
The actions of BDNF are dependent on the activation of an adenosine protein receptor on the cell surface. Modulation of adenosine receptors A1 and A2AR is considered a potential strategy to treat several neurologic disorders such as epilepsy and neurodegenerative diseases. However, it has not been tested in Rett.
Now, researchers based at the University of Lisbon, in Portugal, used a mouse model of Rett to address this knowledge gap and to evaluate whether targeting adenosine receptors could increase the power of BDNF’s effects.
Results showed there were lower levels of BDNF in brain areas known as the hippocampus and the cerebral cortex in the mouse model of Rett compared with healthy mice. Notably, these two brain regions are key for memory and learning, among other functions.
Lower levels of the receptor that BDNF binds for proper function, called TrkB-FL, also were found in the same areas of the brain.
BDNF is known to increase the magnitude of long-term potentiation (LTP), a process in which the connection between two neurons — known as synapses — is strengthened by repeated activation. LTP is essential in the response to experiences, and underlies learning and memory.
However, administration of the BDNF protein to the hippocampus did not increase the magnitude of LTP.
Then, a series of experiments revealed that the ability of adenosine receptors to regulate synaptic function in the mouse model of Rett was compromised. Brain extracts had significantly lower amounts of adenosine in the cortex and hippocampus than in control mice.
Mice engineered to mimic Rett symptoms also showed significantly lower levels of the adenosine receptor A2AR in the cortex. Lower amounts of this receptor also were found in the hippocampus, but the difference was not significant. In contrast, A1 receptor levels were higher in both the cortex and the hippocampus in the mouse model of Rett.
Finally, using BDNF with a small molecule called CGS21680 — which selectively activates A2AR — increased LTP in the hippocampus of the mouse model to a level “comparable to that obtained with BDNF alone in [healthy control] animals,” the investigators wrote.
These results suggested that activation of A2AR with CGS21680 rescued BDNF signaling deficits in hippocampal LTP, which supported the theory that lack of adenosine production “plays a major role in synaptic transmission deficits in [Rett] patients,” the team added.
“In conclusion, we found that BDNF actions upon hippocampal LTP are impaired in [Rett],” the researchers wrote. “Importantly, by understanding that the adenosinergic system is compromised in [Rett syndrome], we can now advance that deregulation of BDNF signalling can also be due to impairment of endogenous A2AR activation.”
“This study thus sets the stage for new adenosine-based pharmacological therapeutic strategies for [Rett], for which disease modifying drugs are still lacking,” they added.