Interestingly, the groups found that the excitatory-inhibitory balance in the cortex of the mice was shifted towards inhibition (decreased brain activity). They surmise that this shift toward inhibition in the cortex and perhaps other brain regions could underlie some of the cognitive, motor, linguistic and social symptoms seen in RTT.
The spontaneous firing of L5 pyramidal neurons in 5 week-old mice was decreased 4-fold when compared to normal mice. This reduction is progressive, since two weeks earlier, in presymptomatic mice, the reduction was only 2-fold. This finding represents the first experimental evidence for a physiological abnormality that exists before symptoms appear.
"It's important to note that since this defect is seen so early it suggests that the reduced cortical activity may be a primary cellular defect that may lead to other neuropathologies," shared Qiang Chang, co-first author on the paper.
Future work will focus on elucidating the mechanisms by which the lack of MECP2 leads to increased inhibition and reduced excitation. "The next step is to use a technique called paired recording to look at the properties of individual synaptic connections between pairs of cortical neurons to find out more precisely which connections change and how. We are also trying to understand which other neural genes are regulated by Mecp2 by measuring gene expression in neurons from knockout mice and their normal siblings," said Sacha Nelson, the corresponding author of the paper.