Neuron Function Reveals Potential Drug Targets for Rare Neurological Disorder

Two studies performed on mice and published in eLife revealed new insight into excitatory and inhibitory neurons that cause symptoms of Rett syndrome.

Rett syndrome is a postnatal neurological disorder that affects about 1 in every 10-12,000 females and is much rarer in males. The disorder is caused by mutations in the MECP2 gene that makes the protein MeCP2, which is essential for the proper function of neurons in the brain.

The 2 major types of neurons in the brain are excitatory neurons, which send signals to other neurons to be active; and inhibitory neurons, which stop or dampen the activity of other neurons to control the rate and timing of incoming information.

In order for the brain to function correctly, it is crucial that the excitatory and inhibitory neurons act in balance with each other, or it can lead to the onset of neurological disorders. Since the 2 types of neurons play a key role in the brain, researchers conducted 2 different studies in mice to examine these roles further.

In the first study, researchers sought to determine whether expressing MeCP2 only in inhibitory neurons would be enough to prevent some or all of the Rett-like symptoms. The results of study revealed that when MeCP2 was expressed only in inhibitory neurons, it increased lifespan and rescued most, but not all, of the behavioral deficits in mice.

“Our data suggest that when a brain is missing MeCP2 everywhere, turning on the gene in inhibitory neurons can make the brain network nearly normal and prevent most Rett-like symptoms,” said lead study author Kerstin Ure. “However, when both normal cells and cells with mutated MeCP2 are present in the same brain, as seen in female mutant mice, the abnormalities caused by this mixture cannot be overcome just by rescuing the function of inhibitory neurons. This highlights the importance of doing future studies in female mice to better understand how Rett syndrome develops.”

The first study’s findings were taken into account when the authors of the second study wanted to discover what aspects of the syndrome would appear or recover if MeCP2 was removed or re-expressed in excitatory neurons.

The results of the second study showed that removing MeCP2 only from excitatory neurons contributed to the onset of several Rett-like symptoms, some of which were distinct and complementary to those mediated by inhibitory neurons.

“We showed that mice lacking the gene from these neurons develop tremor and anxiety-like behaviors, abnormal seizure-like brain activity, severe obesity, and early death, which is surprisingly different from mice missing MeCP2 in inhibitory neurons,” said the second study’s lead author Xiangling Meng. “When the gene was re-expressed in excitatory neurons, the female mice were almost completely recovered. In the case of more severe mice, their anxiety and tremors were rescued, suggesting that impairment of excitatory neurons by removing MeCP2 contributes to the onset of specific symptoms such as these.”

The findings from the 2 studies provided further insight into Rett syndrome and the MeCP2 gene.

“Together, our findings show that rescuing the activity of MeCP2 in certain cell types can have a profound effect on improving symptoms,” said senior author of both papers, Huda Zoghbi.

Researchers next plan to investigate whether drugs that improve the function of inhibitory and excitatory neuron activity could be used to treat Rett syndrome. Future studies will primarily focus on improving neuron function in hopes of potentially restoring balance.

“For now, we are looking at different ways of activating inhibitory neurons in the female mouse brain, including testing drugs and special channels that can activate a cell when a specific chemical is given to the mice,” Zoghbi said. “We hope these methods will help us refine a path forward for potential new therapies for patients.”