Research Focus

Research Focus

japanese

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Learning and memory, which are higher brain functions, are formed on the basis of a basic neural function called synaptic plasticity. In the mammalian brain, including humans, glutamate is the main neurotransmitter, and its receptors, glutamate receptors, play a central role not only in normal neural functions but also in higher brain functions. During the past decade, many synaptic molecules have been discovered and much effort has been invested in understanding how these molecules function in neurons. Glutamate receptors, such as N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors, have been intensively studied because they are the primary excitatory neurotransmitter receptors in the central nervous system. Following the discovery of long-term potentiation (LTP) and long-term depression (LTD) many investigators have scrutinized the molecular mechanisms underlying these forms of plasticity, which are thought to be critical for memory and learning. Elucidation of the molecular mechanisms influencing synaptic plasticity will provide a better understanding of higher brain function.
In our laboratory, we aim to elucidate the formation mechanism of higher brain functions centered on these glutamate receptors, and to understand diseases caused by their disorders. Furthermore, our goal is to develop approaches to recover lost brain functions.

1. Molecular mechanisms of synaptic plasticity, the basis of memory and learning

Glutamate, a neurotransmitter, plays a central role in neurotransmission in the central nervous system, but its receptors are modified as various proteins. Glutamate, a neurotransmitter, plays a central role in neurotransmission in the central nervous system, but its receptors are modified as various proteins, which alter receptor function and affect neurotransmission. They also modulate synaptic plasticity, an important neural function, which in turn affects higher brain functions such as learning and memory. In our laboratory, we are investigating how protein modifications of glutamate receptors, which are mainly involved in neurotransmission in the central nervous system, affect higher brain functions such as learning and memory. In recent years, we have been trying to clarify the various effects of glycosylation of glutamate receptors on neurological functions such as learning, memory, and psychiatric disorders. In addition, it has been shown that the memories of parents are transmitted to their children, and the children reproduce the same memories when they are exposed to the same stimuli as their parents. We are analyzing the mechanism by which this occurs through long-term animal experiments.

2. Brain mechanisms in developmental disorders

In recent years, autism spectrum disorder, ADHD, and learning disabilities have become increasingly problematic as developmental disorders in childhood. Currently, we are conducting analysis based on the hypothesis that dyslexia, which is one of the learning disabilities, may be caused by a defect in the formation of brain networks due to the causative gene found in the brain. In addition, we are analyzing how neurotransmission and synaptic plasticity are impaired by genetic mutations of glutamate receptors, which have been reported in mental retardation.

3. Repair of damaged brains by neural regeneration

Recent research, including iPS cells, has led to rapid progress in technology that can induce other cells to become neurons. In this laboratory, we are trying to introduce foreign genes into glial cells, which are abundant in the brain, in order to differentiate them into nerve cells and regenerate mature nerve cells with advanced neurological functions. These techniques may have the potential to restore neurological functions lost due to Alzheimer's disease or cerebral infarction.

As our long term goal, we will pursue studying the molecular mechanism of synaptic plasticity described above to understand how brain functions are regulated at the molecular level. Additionally, we desire to perform research that is relevant to aiding the recovery of higher neuronal function after various brain damage, such as from epilepsy, stroke, and degenerative disease. We would like to continue my work directed toward this long-term goal.

Keywords: glutamate receptors, synaptic plasticity, glycosylation, learning and memory, developmental disorders, memory inheritance, neural regeneration

References

  • Midorikawa R., Takakura D., Morise J., Wakazono Y., Kawasaki N., Oka S.,Takamiya K.:Monitoring the glycosylation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate-type glutamate receptors using specific antibodies reveals a novel regulatory mechanism of N-glycosylation occupancy by molecular chaperones in mice, Journal of Neurochemistry153:567-585, 2020
  • Morise J., Suzuki K.G.N., Kitagawa A., Wakazono Y., Takamiya K., Tsunoyama T.A., Nemoto Y.L., Takematsu H., Kusumi A., Oka S.:AMPA receptors in the synapse turnover by monomer diffusion, Nature Communications 10:5245, 2019
  • Kandel M.B., Yamamoto S., Midorikawa R., Morise J., Wakazono Y., Oka S., Takamiya K.: N-glycosylation of the AMPA-type glutamate receptor regulates cell surface expression and tetramer formation affecting channel function, Journal of Neurochemistry 147: 730-747, 2018
  • Takamiya K, Mao L, Huganir RL, Linden DJ.: The GRIP family of GluR2-binding proteins is required for LTD expression in cerebellar Purkinje cells. J Neuroscinece 28:5752-5. 2008
  • Steinberg JP*, Takamiya K*, Shen Y, Xia J, Rubio ME, Yu S, Jin W, Thomas GM,Linden DJ, Huganir RL.: Targeted in vivo mutations of the AMPA receptor subunit GluR2 and its interacting protein PICK1 eliminate cerebellar long-term depression. Neuron 49:845-60. 2006 *Equal contribution
  • Takamiya K, Kostourou V, Adams S, Jadeja S, Chalepakis G, Scambler PJ,Huganir RL, Adams RH.: A direct functional link between the multi-PDZ domain protein GRIP1 and the Fraser syndrome protein Fras1. Nat Genet 36:172-7. 2004
  • Lee HK*, Takamiya K, * Han JS, Man H, Kim CH, Rumbaugh G, Yu S, Ding L, He C,Petralia RS, Wenthold RJ, Gallagher M, Huganir RL.: Phosphorylation of the AMPA receptor GluR1 subunit is required for synaptic plasticity and retention of spatial memory. Cell 112:631-43. 2003 *Equal contribution
  • 宮崎大学
  • 宮崎大学医学部

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