Early cerebellum injury hinders neural development, possible root of autism, theory suggests

A brain region largely known for coordinating motor control has a largely overlooked role in childhood development that could reveal information crucial to understanding the onset of autism, according to Princeton University researchers.

The cerebellum — an area located in the lower rear of the brain — is known to process external and internal information such as sensory cues that influence the development of other brain regions, the researchers report in the journal Neuron. Based on a review of existing research, the researchers offer a new theory that an injury to the cerebellum during early life potentially disrupts this process and leads to what they call “developmental diaschisis,” which is when a loss of function in one part of the brain leads to problems in another region.

The researchers specifically apply their theory to autism, though they note that it could help understand other childhood neurological conditions. Conditions within the autism spectrum present “longstanding puzzles” related to cognitive and behavioral disruptions that their ideas could help resolve, they wrote. Under their theory, cerebellar injury causes disruptions in how other areas of the brain develop an ability to interpret external stimuli and organize internal processes, explained first author Sam Wang, an associate professor of molecular biology and the Princeton Neuroscience Institute (PNI).

"It is well known that the cerebellum is an information processor. Our neocortex [the largest part of the brain, responsible for much higher processing] does not receive information unfiltered. There are critical steps that have to happen between when external information is detected by our brain and when it reaches the neural cortex," said Wang, who worked with doctoral student Alexander Kloth and postdoctoral research associate Aleksandra Badura, both in PNI.

"At some point, you learn that smiling is nice because Mom smiles at you. We have all these associations we make in early life because we don’t arrive knowing that a smile is nice," Wang said. "In autism, something in that process goes wrong and one thing could be that sensory information is not processed correctly in the cerebellum."

Mustafa Sahin, a neurologist at Boston’s Children Hospital and associate professor of neurology at Harvard Medical School, said that Wang and his co-authors build upon known links between cerebellar damage and autism to suggest that the cerebellum is essential to healthy neural development. Numerous studies — including from his own lab — support their theory, said Sahin, who is familiar with the work but was not involved in it.

"The association between cerebellar deficits and autism has been around for a while," Sahin said. "What Sam Wang and colleagues do in this perspective article is to synthesize these two themes and hypothesize that in a critical period of development, cerebellar dysfunction may disrupt the maturation of distant neocortical circuits, leading to cognitive and behavioral symptoms including autism."

Traditionally, the cerebellum has been studied in relation to motor movement and coordination in adults. Recent studies, however, strongly suggest that it also influences childhood cognition, Wang said. Several studies also have found a correlation between cerebellar injury and the development of a disorder in the autism spectrum, the researchers report. For instance, the researchers cite a 2007 paper in the journal Pediatrics that found that individuals who experienced cerebellum damage at birth were 40 times more likely to score highly on autism screening tests. They also reference studies in 2004 and 2005 that found that the cerebellum is the most frequently disrupted brain region in people with autism.

"What we realized from looking at the literature is that these two problems — autism and cerebellar injury — might be related to each other" via the cerebellum’s influence on wider neural development, Wang said. "We hope to get people and scientists thinking differently about the cerebellum or about autism so that the whole field can move forward."

The researchers conclude by suggesting methods for testing their theory. First, by inactivating brain-cell electrical activity, it should be possible to pinpoint the developmental stage in which injury to one part of the brain affects the maturation of another. A second, more advanced method is to reconstruct the neural connections between the cerebellum and other brain regions; the federal BRAIN Initiative announced in 2013 aims to map the activity of all the brain’s neurons. Finally, mouse brains can be used to disable and restore brain-region function to observe the “upstream” effect in other areas.

Scientists Discover Key Signaling Pathway that Makes Young Neurons Connect

Neuroscientists at The Scripps Research Institute (TSRI) have filled in a significant gap in the scientific understanding of how neurons mature, pointing to a better understanding of some developmental brain disorders.

In the new study, the researchers identified a molecular program that controls an essential step in the fast-growing brains of young mammals. The researchers found that this signaling pathway spurs the growth of neuronal output connections by a mechanism called “mitochondrial capture,” which has never been described before.

“Mutations that may affect this signaling pathway already have been found in some autism cases,” said TSRI Professor Franck Polleux, who led the research, published June 20, 2013 in the journal Cell.

Branching Out

Polleux’s laboratory is focused on identifying the signaling pathways that drive neural development, with special attention to the neocortex—a recently evolved structure that handles the “higher” cognitive functions in the mammalian brain and is highly developed in humans.

In a widely cited study published in 2007, Polleux’s team identified a trigger of an early step in the development of the most important class of neocortical neurons. As these neurons develop following asymmetric division of neural stem cells, they migrate to their proper place in the developing brain. Meanwhile they start to sprout a root-like mesh of input branches called dendrites from one end, and, from the other end, a long output stalk called an axon. Polleux and his colleagues found that the kinase LKB1 provides a key signal for the initiation of axon growth in these immature cortical neurons.

In the new study, Polleux’s team followed up this discovery and found that LKB1 also is crucially important for a later stage of these neurons’ development: the branching of the end of the axon onto the dendrites of other neurons.

“In experiments with mice, we knocked the LKB1 gene out of immature cortical neurons that had already begun growing an axon, and the most striking effect was a drastic reduction in terminal branching,” said Julien Courchet, a research associate in the Polleux laboratory who was a lead co-author of the study. “We saw this also in lab dish experiments, and when we overexpressed the LKB1 gene, the result was a dramatic increase in axon branching.”

Further experiments by Courchet showed that LKB1 drives axonal branching by activating another kinase, NUAK1. The next step was to try to understand how this newly identified LKB1-NUAK1 signaling pathway induced the growth of new axon branches.

Stopping the Train in Its Tracks

Following a thin trail of clues, the researchers decided to look at the dynamics of microtubules. These tiny railway-like tracks are laid down within axons for the efficient transport of molecular cargoes and are altered and extended during axonal branching. Although they could find no major change in microtubule dynamics within immature axons lacking LKB1 or NUAK1, the team did discover one striking abnormality in the transport of cargoes along these microtubules. Tiny oxygen-reactors called mitochondria, which are the principal sources of chemical energy in cells, were transported along axons much more actively—and by contrast, became almost immobile when LKB1 and NUAK1 were overexpressed.

But the LKB1-NUAK1 signals weren’t just immobilizing mitochondria randomly. They were effectively inducing their capture at points on the axons where axons form synaptic connections with other neurons. “When we removed LKB1 or NUAK1 in cortical neurons, the mitochondria were no longer captured at these points,” said Tommy Lewis, Jr., a research associate in the Polleux Laboratory who was co-lead author of the study.

“We argue that there must be an active ‘homing factor’ that specifies where these mitochondria stop moving,” said Polleux. “And we think that this is essentially what the LKB1-NAUK1 signaling pathway does here.”

Looking Ahead

Precisely how the capture of mitochondria at nascent synapses promotes axonal branching is the object of a further line of investigation in the Polleux laboratory. “We think that we have uncovered something very interesting about mitochondrial function at synapses,” Polleux said.

In addition to its basic scientific importance, the work is likely to be highly relevant medically. Developmentally related brain disorders such as epilepsy, autism and schizophrenia typically involve abnormalities in neuronal connectivity. Recent genetic surveys have found NUAK1-related gene mutations in some children with autism, for example. “Our study is the first one to identify that NUAK1 plays a crucial role during the establishment of cortical connectivity and therefore suggests why this gene might play a role in autistic disorder,” Polleux says.

He notes, too, that declines in normal mitochondrial transport within axons have been observed in neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. “In the light of our findings, we wonder if the decreased mitochondrial mobility observed in these cases might be due not to a transport defect, but instead to a defect in mitochondrial capture in aging neurons,” he said. “We’re eager to start doing experiments to test such possibilities.”

(Image: Shutterstock)

Clues to Fetal Alcohol Risk: Molecular switch promises new targets for diagnosis and therapy

Fetal alcohol syndrome is the leading preventable cause of developmental disorders in developed countries. And fetal alcohol spectrum disorder (FASD), a range of alcohol-related birth defects that includes fetal alcohol syndrome, is thought to affect as many as 1 in 100 children born in the United States.

Any amount of alcohol consumed by the mother during pregnancy poses a risk of FASD, a condition that can include the distinct pattern of facial features and growth retardation associated with fetal alcohol syndrome as well as intellectual disabilities, speech and language delays, and poor social skills. But drinking can have radically different outcomes for different women and their babies. While twin studies have suggested a genetic component to susceptibility to FASD, researchers have had little success identifying who is at greatest risk or what genes are at play.

Research from Harvard Medical School and Veterans Affairs Boston Healthcare System sheds new light on this question, identifying for the first time a signaling pathway that might determine genetic susceptibility for the development of FASD. The study was published online Feb. 19 in the journal Proceedings of the National Academy of Sciences.

“Our work points to candidate genes for FASD susceptibility and identifies a path for the rational development of drugs that prevent ethanol neurotoxicity,” said Michael Charness, chief of staff at VA Boston Healthcare System and HMS professor of neurology. “And importantly, identifying those mothers whose fetuses are most at risk could help providers better target intensive efforts at reducing drinking during pregnancy.”

The discovery also solves a riddle that had intrigued Charness and other researchers for nearly two decades. In 1996, Charness and colleagues discovered that alcohol disrupted the work of a human protein critical to fetal neural development—a major clue to the biological processes of FASD. The protein, L1, projects through the surface of a cell to help it adhere to its neighbors. When Charness and his team introduced the protein to a culture of mouse fibroblasts cells, L1 increased cell adhesion. Tellingly, the effect was erased in the presence of ethanol (beverage alcohol).

Charness and his team went on to develop multiple cell lines from that first culture, and that’s where they encountered the riddle: In some of those lines, alcohol disrupted L1’s adhesive effect, while in others it did not.

“How could it be possible that a cell that expresses L1 is completely sensitive to alcohol, and others that express it are completely insensitive?” asked Charness, who is also faculty associate dean for veterans hospital programs at HMS and assistant dean at Boston University School of Medicine.

Clearly, something else was affecting the protein’s sensitivity to alcohol — but what? Studies of twins provided one clue: Identical twins are more likely than fraternal twins to have the same diagnosis, positive or negative, for FASD. “That concordance suggests that there are modifying genes, susceptibility genes, that predispose to this condition,” Charness said.