Plasticity Depends on Transcription Factor Traveling Cell to Cell
In the months and years after a much-loved child is born, attentive parents marvel at their many distinct spurts in mental skills. Babies’ eyes begin to focus and soon track moving people and objects. They respond to spoken language before they can utter their first intelligible sounds. In succession, kids can read single letters, then words. Soon, they compose whole sentences and eventually devour the latest Harry Potter book.
These windows of accelerated learning, known as critical periods, seem even more amazing from the perspective of an adult, whose brain woefully struggles in comparison to learn new things. Acquiring a foreign language is much easier before age 11, for example.
Now researchers have discovered an unusual molecular wake-up call that triggers heightened plasticity in the visual cortex in the first month after birth, reports a paper in the Aug. 8 Cell. In one surprise, the brain responds to an outside cue—in this case, eyes opening for the first time—rather than dictating the timing from within. More unexpected is the nature of the cue and the way it works.
When the eyelids of baby mice first flutter open, researchers found, the retinas flood the synaptic highway into the visual cortex with molecules called OTX2. The molecules jump from neuron to neuron to the back of the brain. Once there, they turn on the specific circuitry to rewire the brain for sight.
“The eyes are sending more than neural images and electric signals. They are sending a molecular messenger that switches on the plasticity process,” said senior author Takao Hensch, professor of neurology at Children’s Hospital Boston and Harvard Medical School. “It’s quite a distance to go.”
The phenomenon may apply more broadly, scientists speculate. Similar proteins from the ear, nose, or skin at different times may open plasticity in the auditory, olfactory, and other sensory regions in the brain.
“This paper establishes a key new mechanism where activity in one part of the brain [the retina] can control plasticity in another [the cortex],” said Michael Shelanski, codirector of the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at Columbia University, who was not involved in the study. “Neuronal plasticity is required for learning and for repair in the nervous system.”
The authors see therapeutic potential down the road. “It’s a bit of a science fiction now, but the fact that we can access the brain mechanism of plasticity from the periphery gives us a new route of entry for brain therapies,” Hensch said. He envisions delivering tiny specialized proteins to boost development of specific cells whose impairment may cause disorders ranging from vision loss to schizophrenia.
The study has its roots in conversations between Hensch and French neuroscientist Alain Prochiantz, a collaborator and senior co-author. Prochiantz’s lab studies transcription factors called homeoproteins, best known for directing the precise placement of body parts in developing embryos. In neuron cell cultures, Prochiantz discovered, these factors could be secreted and internalized by neurons to regulate development of their neighbors. In fact, the same short section of protein that binds DNA also allows homeoproteins to slip through cell membranes, his lab showed. The 200 or so homeoproteins all share a version of that cell-penetrating domain, plus another conserved piece allowing translation regulation (not just transcription). Prochiantz and his colleagues proposed the homeoproteins were also used for direct cell signaling.
“It was a heretical idea that homeoproteins might pass from cell to cell in biology, but the fact is, they do,” Hensch said. After all, the job of the transcription factor in developing embryos is to define borders and boundaries in embryos, not spill over and cross them. Many scientists dismissed the work as an experimental artifact. Hensch and Prochiantz teamed up to explore the physiological relevance in vivo.
Meanwhile, in another paradox, Hensch had shown that the window of visual plasticity begins with the maturing of a group of cells that release the inhibitory neurotransmitter GABA. Specifically, plasticity begins with PV basket cells, named for the basketlike connections they make around the cell body of neighboring neurons.
“Plasticity is critical after the circuit is wired up [in development],” Hensch said. “We know that PV cells trigger a pruning process between excitatory cells, followed by growth [of remaining connections]. These are times in life when sensory inputs are bombarding the brain, and the neurocircuitry is rewiring itself to best represent the world in which it is found.”
For his research in mice, Hensch adapted a well-studied animal model of brain plasticity that was first developed in the Nobel Prize–winning studies of HMS researchers David Hubel and Torsten Wiesel. If one eye is deprived of visual inputs during its critical period, the unencumbered eye gains more neuronal turf at the expense of the deprived eye.
The homeoprotein OTX2 loomed as an ideal candidate for the two labs to test. In developing embryos, the transcription factor crucially delivers a fully articulated brain. OTX2 lurks throughout the visual pathway during its development. It disappears from the visual cortex two weeks after birth in mice, but lingers in the retina, where it helps lay down photoreceptors and bipolar cells.
Using molecular tools from the Prochiantz lab, postdoctoral fellow Sayaka Sugiyama found OTX2 returned to the visual cortex beginning about day 21 and congregated almost exclusively to the GABA-releasing PV cells. In contrast, mice raised in absolute darkness showed no sign of OTX2 in the PV cells, plus delayed plasticity. Sugiyama could speed up or postpone the critical period by changing OTX2 transport to the PV cells.
In mature PV neurons, Sugiyama found no mRNA evidence of OTX2 expression, but specially-tagged OTX2 injected into the retina showed up a few days later in the PV neurons. OTX2 action in the visual cortex diminished following surgical removal of the eye or a knockdown of the OTX2 gene in the retina.
Most intriguing to Sugiyama is the persistent OTX2 in the adult visual cortex. The cumulative OTX2, apparently held in store by netlike structures around PV neurons, inhibits plasticity in adults. When the netlike structures are dissolved, PV neurons reactivate the puplike plasticity in adult mice.
The results are “provocative” and “groundbreaking,” write Z. Josh Huang and Graziella Di Cristo in a commentary in the Aug. 14 Neuron, a sister journal to Cell.
Conflict Disclosure: The authors declare no conflicts of interest.
Funding Sources: The Human Frontiers Science Program (Strasbourg), the Fondation pour La Recherche Medicale, and in part by RIKEN (Japan) and the Japanese Ministry of Science, Education and Technology (MEXT)