Loss of genes keeps brain’s neural circuits from reorganizing in maturing mice.
Scientists report in the journal Neuron the lost function of two genes prevents infant laboratory mice from developing motor skills as they mature into adults. Researchers also suggest in their study that people with certain motor development disabilities be tested to see if they have mutant forms of the same genes.

In a study published May 3, researchers from Cincinnati Children’s Hospital Medical Center and the City University of New York School of Medicine show that neural circuits between the brain’s motor cortex region and the spinal cord did not properly reorganize in maturing mice. The circuits are part of the cortical spinal network, which coordinates the activation of muscles in limbs.

Researchers bred the mice to lack molecular signaling from the Bax/Bak genetic pathway. Investigators demonstrated in a variety of experiments how Bax/Bak’s downstream molecular targets are vital to developing appropriately sophisticated connections between the motor cortex, spinal circuits and opposing extensor/flexor muscle groups in the animals.

“If mutations in the Bax/Bak pathway are found in human patients with developmental motor disabilities, these findings could be very translational to possible medical application,” said Yutaka Yoshida, PhD, study lead author and a member of the Division of Developmental Biology at Cincinnati Children’s. “Our goal is for future studies to determine whether disruptions in Bax/Bak pathway are implicated in some people with skilled motor disabilities and whether it also regulates reorganization of other circuits in the mammalian central nervous system.”

Collaborating on the study with Yoshida was John Martin, PhD, co–lead author at the City University of New York School of Medicine, Department of Physiology, Pharmacology and Neuroscience.

The researchers stress that because the study was conducted with mice, additional research is required before it can be confirmed whether the data apply directly to human health. Young postnatal mammals, including human babies, can perform only basic unskilled motor tasks. Citing a number of previous studies on this point, authors of the current paper write one reason for this is that infantile neural circuitry is wired to activate antagonistic (or opposing) muscles at the same time.

People with developmental dyspraxia may appear "out of sync" with their environment and symptoms can vary, including: poor balance and coordination, clumsiness, vision problems, perception difficulties, emotional and behavioral problems, difficulty with reading, writing, and speaking, poor social skills, poor posture, and poor short–term memory. Although people with the disorder can be of average or above average intelligence, they may move their limbs immaturely.

To explore connections between corticospinal neurons in the mouse brain’s motor cortex and muscles – and to identify genetic pathways involved in their development – scientists in the journal Neuron study used trans–synaptic viral and electrophysiological assays. This allowed them to observe and trace how these connections develop in maturing mice.

Trans–synaptic tracing in the current study highlighted how the presence of Bax/Bak signaling resulted in sophisticated circuity as mice matured. It also triggered the development of circuits that allowed opposing muscle groups to activate reciprocally. The absence of Bax/Bak signaling resulted in continued formation of inappropriate circuitry that did not allow reciprocal activation of these muscles.