Mouse model of Rett Syndrome displays reduced cortical activity

Sacha Nelson of Brandeis University in Waltham, MA and Rudolf Jaenisch of the Whitehead Institute of Biomedical Research in Cambridge, MA and their colleagues report online in the Proceedings of the National Academy of Sciences Early Edition that spontaneous neuronal activity is reduced in the cortex of a knockout mouse model for the childhood neurodevelopmental disorder, Rett Syndrome. The Rett Syndrome Research Foundation (RSRF) and the McKnight Foundation funded this project.

Rett Syndrome (RTT) is a severe neurological disorder diagnosed almost exclusively in girls. Children with RTT appear to develop normally until 6 to 18 months of age, when they enter a period of regression, losing speech and motor skills. Most develop repetitive hand movements, irregular breathing patterns, seizures and extreme motor control problems. RTT leaves its victims profoundly disabled, requiring maximum assistance with every aspect of daily living. There is no cure.

The nervous system consists of billions of neurons that communicate with each other. Neurons don't touch and the gap between them is called a synapse. This gap is bridged by neurotransmitters that are released by the generation of electrical signals. Some neurotransmitters are excitatory and increase activity in the brain and others are inhibitory and decrease activity. In healthy brains, a balance between excitation and inhibition is essential for nearly all functions, including representation of sensory information, cognitive processes such as decision making, sleep and motor control.

The electrical signals that neurons generate can be measured using microelectrodes. Using a technique called, whole cell patch clamp, Vardhan Dani, a graduate student in Dr. Nelson's lab and Qiang Chang a post doctoral fellow from Rudolf Jaenisch's lab tested the electrical impulses in the cortex of the Rett Syndrome knockout mouse model. The cortex is one of the regions of the brain affected in patients with RTT. These mice are genetically manipulated so they lack the "Rett gene", MECP2. Like individuals with Rett Syndrome, they are seemingly normal at birth and begin to exhibit Rett-like behaviors by 5 weeks of age.

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.