A study in mice suggests that birth is a “critical period” in Rett syndrome (RTT), with neuronal alterations already present at that stage that might be reduced by early treatment of mothers.
The study, “Early alterations in a mouse model of Rett syndrome: the GABA developmental shift is abolished at birth,” was published in the journal Scientific Reports.
Whether Rett syndrome is associated with early developmental alterations “is clearly a complex and controversial issue.” Developmental processes are often considered irrelevant for the disease but the fact is that neuronal activity at birth has never been recorded.
To fill this gap, the researchers performed electrical recordings in neurons of mouse models of Rett syndrome immediately after birth, and found that certain biological pathways in the brain are already altered at birth and early after. The mouse model used was deficient for the MECP2 gene, the main genetic cause underlying Rett syndrome.
One of the most important observations was that a neurological process that naturally occurs early in life, termed GABA developmental shift, was abolished in newborn Rett mice.
GABA is the main inhibitory neurotransmitter in the adult brain. In other words, it is the main chemical messenger responsible for blocking the transmission of nerve impulses and decreasing the activity of our nervous system.
However, it has a very peculiar characteristic. Contrary to its activity in the adult brain, GABA works as an excitatory neurotransmitter in the early days of life. In the fetus, at birth and in the short period thereafter, GABA increases calcium concentrations inside neurons and triggers electrical impulses. During this postnatal period, GABA signals undergo a switch from being excitatory to inhibitory.
The importance of GABA to our nervous system is underlined by the fact that many neurological disorders, such as seizures, anxiety, autism, and Parkinson’s disease, have been related to imbalances in GABA activity.
Indeed, Rett mice were affected by long-term GABA excitatory actions “that might directly or indirectly lead to long-term deleterious sequels,” the researchers stated.
Scientists treated pregnant female mice one day before delivery with bumetanide and observed this restored GABA normal (inhibitory) activity and related networks; however, it did not rescue deficiencies in breathing patterns or weight, or onset of mortality.
Bumetanide helps reduce the number of chloride ions inside cells. It has recently been proposed as a novel therapy for attenuating neurological and psychiatric disorders. Currently, bumetanide is FDA-approved under the brand Bumex as a diuretic to treat fluid retention.
Indeed, in recent studies, the same team had shown that bumetanide reduced the severity of autism spectrum disorders (ASD) in two animal models and in children.
“As [Rett] includes cognitive ASD-like symptoms, bumetanide treatment in pilot trials might alleviate some of the manifestations present in [Rett] patients,” the researchers said.
“Although we do not know how administration of a drug restricted to the critical period of birth leads to such long-term effects, understanding the developmental alterations associated with this period is instrumental in a therapeutic perspective,” they added.
Nevertheless, researchers say it becomes apparent from their study that “developmental sequences are of clear importance in the [disease mechanisms of Rett] and must be investigated as early as birth.”