What is your goal?

My goal is to elucidate “the molecular mechanism of synaptic circuit development in the brain.” Allow me to provide a simple explanation of the background on this subject of research.

Canaries form lifelong singing styles through their hearing experiences and subsequent practice as young birds. Naturally, in humans, with more developed cerebrum, childhood growth environments and lifestyle backgrounds have an extraordinary influence on the rest of their lives in a variety of ways. For example, the language of the region in which they spent their childhood naturally becomes their mother tongue, and their daily life activities become habitual. Moreover, professionals with unmatched athletic skills, musical performance techniques, or reasoning abilities that surpass even computers emerge from those who have continued to practice sports, musical instruments, or the games of Go and Japanese chess since their youth. Such significant improvement in physical and intellectual abilities is achieved through a severe battle of survival in the brain, in which synaptic circuits, activated by sensory stimulation received from their surroundings, are expanded and strengthened, while other inferior synaptic circuits are weakened and removed (Figure 1).

Figure 1. Reconstruction of synaptic circuits developed in the critical period (sensitive period). Immature neural circuits with a lot of overlapping in the neonatal stage undergo trimming, expansion, and reduction with activated sensory stimulations in the critical period, followed by the reconstruction of functional neural circuits, which reflects the subject’s life history.

 

Such reconstruction of synaptic circuits occurs efficiently during the critical period, or the so-called sensitive period, after which it becomes less likely to occur. The significance of the critical period has been recognized since ancient times, and as indicated by sayings such as, “Send young children out on journeys (so that they can experience some degree of difficulty while young),” “As the boy, so the man,” and “Make your child learn reading, writing, and arithmetic,” nations, local societies, and parents have been practicing this idea through private elementary schools and at home. We are investigating the trimming of synaptic circuits and plastic molecular mechanisms promoted via the acceptance and transmission of sensory stimulation. Furthermore, we aim to elucidate the molecular mechanism involved in maintaining functional synaptic circuits reconstructed in childhood for one’s lifetime throughout the adult stage.

What kind of experiments are you conducting and what types of equipment are you using?

The most important part of our research strategy is not the equipment but rather gene knockout mice, in which specific genes have been damaged, causing the molecular function thereof to become deficient, or genetically engineered mice that are able to transiently induce or inhibit the expression of certain genes. Using these model animals, we visualize the abnormalities of circuits associated with molecular deficiencies using a variety of microscopes, and electrophysiologically investigate the functional circuit abnormalities in order to determine which phase of the reconstruction process of synaptic circuits is related to that specific molecule. As described below, we have demonstrated that the removal of molecules and receptors of the signal transduction substance, glutamate, which transfers sensory stimulations to the brain, and inhibits competitive trimming, expansion, and reduction of circuits in the critical period.

Figure 2. Competitive development of cerebellar circuits by parallel fibers and climbing fibers. The glutamate receptor GluRd2 strengthens the domination of parallel fibers while restricting the domination of climbing fibers, thereby forming and maintaining territorialized functional neural circuits.

Figure 3. Circuit development in the cerebrum, in which signals of the sensory information are transduced. Expansion and reduction of circuits based on activities are less likely to occur when the transporter molecules that remove glutamate are defective.

What is your next goal?

Based on study results obtained in the past, we have demonstrated that the function to transfer neural signals to the brain, by appropriately reflecting signals in terms of quality and quantity, activates the reconstruction of synaptic circuits in the childhood, after which synaptic circuits are maintained by the molecular mechanism in the adulthood. Regarding the next step, we are interested in the “mechanism for appropriately transferring neural signals to the brain, in terms of quality and quantity,” which is the basis of signal transduction itself. Of course, “the molecular mechanism for the development of synaptic circuits” has merely started to be revealed; therefore, in the future, with these two study objectives, I am looking forward to studying with you at the Hokudai campus where you can enjoy a sense of the seasons. I hope to see students with a sparkle in their eyes come to Hokudai and share time learning and studying together. 

References

(1) Takasaki C, Okada R, Mitani A, Fukaya M, Yamasaki M, Fujihara Y, Shirakawa T, Tanaka K, Watanabe M: Glutamate transporters regulate lesion-induced period plasticity in the developing somatosensory cortex. J. Neurosci. 28:4995-5006, 2008.

(2) Watanabe M, Kano M: Climbing fiber synapse elimination in cerebellar Purkinje cells. Eur. J. Neurosci., 34:1697-1710, 2011.