Research Summary

My laboratory's approach to understand the brain is to reduce the brain to various components and ultimately molecules. Temporally, neurotransmission by a major excitatory neurotransmitter, glutamate, is very quick and is clearly essential for brain function; however, the modulation of brain function underlying learning, memory, emotion, cognition, etc., happens on a different time scale than that of neurotransmission. Our broad goal is to understand how basic synaptic transmission can be modulated over seconds to hours, thereby supporting complex brain functions. The efficacy of synaptic transmission is determined by glutamate concentration at the synaptic cleft and by the number and channel properties of the glutamate receptors, which can be modulated by neuronal activation (synaptic plasticity). We have uncovered a network of modulatory proteins for glutamate receptors to control their number and properties. By understanding the machinery that controls the number and channel properties of glutamate receptors, we hope to reveal the principal rules governing synaptic transmission and synaptic plasticity.

Specialized Terms: Synaptic transmission; Brain; Biochemistry; Molecular biology; Immunocytochemistry; Gene-targeted animals; Electrophysiology

Extensive Research Description

My laboratory’s approach to understand brain is to reduce brain to various components and ultimately molecules. The primary functional component of brain is the neural circuit, which are comprised of anatomical neuronal wiring and synaptic transmission. Temporally, neurotransmission by a major excitatory neurotransmitter in brain, glutamate, is very quick and is clearly essential for brain function; however, the modulation of brain function underlying learning, memory, emotion, cognition, etc., happens on a different time scale than that of neurotransmission. Our broad goal is to understand how basic synaptic transmission can be modulated over seconds to hours, thereby supporting complex brain functions.The efficacy of synaptic transmission is determined by glutamate concentration at the synaptic cleft and by the number and channel properties of the glutamate receptors, which can be modulated by neuronal activation (synaptic plasticity).

It is therefore important to determine how many receptors are at synapses and how strongly these receptors are activated upon glutamate releases. We have uncovered a network of modulatory proteins for glutamate receptors to control their number and properties. By understanding the machinery that controls the number and channel properties of glutamate receptors, we hope to reveal the principal rules governing synaptic transmission and synaptic plasticity. Combined with neuronal wiring mapping, this should help us understand a big picture of neural circuits and the momentary changes that occur in neural circuits to control animal behavior.

Selected Publications

• GARLH Family Proteins Stabilize GABAA Receptors at Synapses.

  Yamasaki T, Hoyos-Ramirez E, Martenson JS, Morimoto-Tomita M, Tomita S. GARLH Family Proteins Stabilize GABAA Receptors at Synapses. Neuron 2017, 93:1138-1152.e6. 2017

• CaMKII Phosphorylation of TARPγ-8 Is a Mediator of LTP and Learning and Memory.
  Park J, Chávez AE, Mineur YS, Morimoto-Tomita M, Lutzu S, Kim KS, Picciotto MR, Castillo PE, Tomita S. CaMKII Phosphorylation of TARPγ-8 Is a Mediator of LTP and Learning and Memory. Neuron 2016, 92:75-83. 2016
• Distinct Subunit Domains Govern Synaptic Stability and Specificity of the Kainate Receptor.
  Straub C, Noam Y, Nomura T, Yamasaki M, Yan D, Fernandes HB, Zhang P, Howe JR, Watanabe M, Contractor A, Tomita S. Distinct Subunit Domains Govern Synaptic Stability and Specificity of the Kainate Receptor. Cell Reports 2016, 16:531-544. 2016
• Homeostatic control of synaptic transmission by distinct glutamate receptors.
  Yan D, Yamasaki M, Straub C, Watanabe M, Tomita S. Homeostatic control of synaptic transmission by distinct glutamate receptors. Neuron 2013, 78:687-99. 2013
• Cornichons control ER export of AMPA receptors to regulate synaptic excitability.
  Brockie PJ, Jensen M, Mellem JE, Jensen E, Yamasaki T, Wang R, Maxfield D, Thacker C, Hoerndli F, Dunn PJ, Tomita S, Madsen DM, Maricq AV. Cornichons control ER export of AMPA receptors to regulate synaptic excitability. Neuron 2013, 80:129-42. 2013
• PDZ binding of TARPγ-8 controls synaptic transmission but not synaptic plasticity.
  Sumioka A, Brown TE, Kato AS, Bredt DS, Kauer JA, Tomita S. PDZ binding of TARPγ-8 controls synaptic transmission but not synaptic plasticity. Nature Neuroscience 2011, 14:1410-2. 2011
• Distinct functions of kainate receptors in the brain are determined by the auxiliary subunit Neto1.
  Straub C, Hunt DL, Yamasaki M, Kim KS, Watanabe M, Castillo PE, Tomita S. Distinct functions of kainate receptors in the brain are determined by the auxiliary subunit Neto1. Nature Neuroscience 2011, 14:866-73. 2011
• Hippocampal AMPA receptor gating controlled by both TARP and cornichon proteins.
  Kato AS, Gill MB, Ho MT, Yu H, Tu Y, Siuda ER, Wang H, Qian YW, Nisenbaum ES, Tomita S, Bredt DS. Hippocampal AMPA receptor gating controlled by both TARP and cornichon proteins. Neuron 2010, 68:1082-96. 2010
• TARP phosphorylation regulates synaptic AMPA receptors through lipid bilayers.
  Sumioka A, Yan D, Tomita S. TARP phosphorylation regulates synaptic AMPA receptors through lipid bilayers. Neuron 2010, 66:755-67. 2010
• Novel transmembrane accessory subunit modulates kainate-type glutamate receptors.

  Zhang W, St-Gelais F, Grabner CP, Trinidad JC, Sumioka A, Morimoto-Tomita M, Kim KS, Straub C, Burlingame AL, Howe JR, Tomita S. Novel transmembrane accessory subunit modulates kainate-type glutamate receptors. Neuron, 61:385-96, 2009. 2009

• Autoinactivation of neuronal AMPA receptors via glutamate-regulated TARP interaction.
  Morimoto-Tomita M, Zhang W, Straub C, Cho CH, Kim KS, Howe JR, Tomita S. Autoinactivation of neuronal AMPA receptors via glutamate-regulated TARP interaction. Neuron 2009, 61:101-12. 2009
• Two families of TARP isoforms that have distinct effects on the kinetic properties of AMPA receptors and synaptic currents.
  Cho CH, St-Gelais F, Zhang W, Tomita S, Howe JR. Two families of TARP isoforms that have distinct effects on the kinetic properties of AMPA receptors and synaptic currents. Neuron 2007, 55:890-904. 2007