"This paper provides the first evidence that microRNAs have a role at the synapse, allowing for a new level of regulation of gene expression," says senior author Michael Greenberg, PhD, Director of Neuroscience at Children's Hospital Boston. "What we've found is a new mechanism for regulating brain function."
The brain's ability to form and refine synapses allows organisms to learn and respond to their environment, strengthening important synaptic connections, forming new ones, and allowing unimportant ones to weaken. Experiments in Greenberg's lab, done in rats, showed that a microRNA called miR-134 regulates the size of dendritic spines, the protrusions from a neuron's dendrites where synapses form. When neurons were exposed to miR-134, spine volume significantly decreased, weakening the synapse. When miR-134 was inhibited, spines increased in size, strengthening the synapse.
Further experiments showed that miR-134 acts by inhibiting expression of a gene called Limk1, which causes dendritic spines to grow. When neurons were exposed to a growth factor known as brain-derived neurotrophic factor (BDNF), this inhibition was overcome and Limk1 became active again, enhancing spine growth.
Greenberg believes that miR-134 – and other microRNAs his lab is studying – may play a role in fine-tuning cognitive function by selectively controlling synapse development in response to environmental stimuli. "A single neuron can form a thousand synapses," says Greenberg, also a professor of neurology and neuroscience at Harvard Medical School. "If you could selectively control what's happening at one synapse without affecting another, you greatly increase the information storage and computational capacity of the brain."
Greenberg also speculates that miR-134 may be relevant to disorders such as mental retardation and autism. He notes that loss of Limk1 due to a chromosomal deletion is associated with Williams syndrome, and that the BDNF pathway that activates Limk1 includes proteins that are disabled in tuberous sclerosis and Fragile X syndrome. All three genetic disorders can cause cognitive impairment and autistic-like behaviors.
The research was supported by grants from the National Insitute of Neurological Disorders and Stroke, the National Institute of Child Health and Human Development, the Human Frontier Science Program, and the Charles Hood Foundation.
Children's Hospital Boston is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 500 scientists, including eight members of the National Academy of Sciences, nine members of the Institute of Medicine and 10 members of the Howard Hughes Medical Institute comprise Children's research community. Founded as a 20-bed hospital for children, Children's Hospital Boston today is a 347-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Children's also is the primary pediatric teaching affiliate of Harvard Medical School. For more information about the hospital and its research visit: http://www.childrenshospital.org/research/.
Journal
Nature