transmission in the central nervous system is mainly mediated by AMPA type
glutamate receptors. AMPA receptors form tetrameric heteromers of subunits.
Subunits can be classified into two groups based on the structure of their
cytoplasmic tail. GluA1, GluA4 and GluA2long (an alternate splice form of GluR2)
possess long cytoplasmic tails while GluA2 and 3 have short cytoplasmic tail.
There is considerable evidence that synaptic insertion of GluA1-containing AMPA
receptors contributes to the synaptic strengthening observed during LTP (Long
term potentiation) in vitro and experience in vivo.
Previous research Themes
1) Experience-driven synaptic AMPA receptor delivery
I have previously found that whisker
experience drives AMPA receptors into synapses of the developing rat barrel
cortex. This is the first evidence of experience-driven synaptic AMPA receptor
delivery in vivo. This research is the basis of our system to evaluate synaptic
AMPA receptor delivery in vivo.
Takahashi T., Svoboda, K.,
Malinow, R. Experience strengthening transmission by driving AMPA receptors
into synapses. Science 299; 1585-1588, 2003
2) Cross-modal plasticity
Loss of a
sensory input can cause improved function of other intact sensory systems. We
found that visual deprivation induced the elevated function of whisker-barrel
system of juvenile rats. Synaptic AMPA receptor delivery is facilitated in the
barrel cortex of juvenile rats with visual deprivation via increased serotonin
secretion. Since this research proves that compensation-induced enhancement of
intact function after loss of functions accompanies with the facilitation of
AMPA receptors, it is the basis of the development of the compound to
accelerate the rehabilitation after stroke.
Jitsuki S, Takemoto K, Kawasaki T, Tada T, Takahashi A,@Becamel C, Sano
A, Yuzaki M, Zukin RS, Ziff EB, Kessels HW,and Takahashi T. Serotonin mediates
cross-modal@reorganization of cortical circuits.@Neuron 69, 780-792, 2011.
Nakajima W, Jitsuki S, Sano A, Takahashi T.
Sustained Enhancement of Lateral Inhibitory Circuit Maintains Cross Modal
PLoS One, 11(2):e0149068, 2016..
3) Neonatal social isolation disrupts synaptic AMPA receptor delivery
Stressful events during early childhood can induce a malfunctioning
of emotional and cognitive behaviors later in life. We found that neonatal
social isolation disrupts experience-driven synaptic AMPA receptor delivery in
rodent. This research led us to the development of PET probe for AMPA receptors
to visualize AMPA receptors in human.
Miyazaki T, Takase K, Nakajima W, Tada H, Ohya D, Sano A,@Goto T, Hirase
H, Malinow R, Takahashi T.@Disrupted cortical function Underlies behavior@dysfunction
due to social isolation. J Clin Invest.,122(7), 2690-701,2012.
Miyazaki T, Kunii S, Jitsuki S, Sano A, Kuroiwa Y, Takahashi T.@Social
isolation perturbs experience-driven synaptic glutamate receptor subunit
4 delivery in the developing rat barrel cortex. Eur J Neurosci., 37(10):1602-9,
Tada H,Miyazaki T,Takemoto K,Takase K,Jitsuki S,Nakajima W,Koide M,Yamamoto
N,Komiya K, Suyamaa K,Sano A,Taguchi A,and Takahashi T. Neonatal isolation
augments social dominance by altering actin dynamics in the medialprefrontal
PNAS, E7097-E7105, 1606351113, 2016.10
4) Hippocampus dependent learning drives AMPA receptors into CA3-CA1
We have found that hippocampus dependent
contextual fear learning drives AMPA receptors into CA3-CA1
hippocampal synapses via acetylcholine elevation.
Mitsushima D, Ishihara K, Sano A, Kessels HW, Takahashi T. Contaxtual learning
requires synaptic AMPA receptor delivery in the hippocampus. Proc Natl
Acad Sci USA., 108i30j,12503-12508, 2011.
Mitsushima D, Sano A,
Takahashi T. Cholinergic trigger drives learning-induced plasticity at
hippocampal synapses. Nature Communications, Vol 4, Article number 2760,2013.
Current Research Themes
1) Novel drugs to accelerate the recovery of the motor
function with rehabilitation after brain injury (collaboration with FUJIFILM)
Using our in vivo system to evaluate experience-dependent synaptic AMPA
receptor delivery, we discovered a novel drug to facilitate experience-dependent
synaptic AMPA receptor delivery. This drug accelerates motor function recovery
after brain injury (such as stroke) in a training dependent fashion with
rodent. We also detected prominent effects with Macaca. We are now preparing
for the clinical trial. We hope this will decrease the agony of patients
with severe paralysis and minimize the economic burden.
2) Development of PET probe to
visualize AMPA receptors in human
Recent advance in rodent physiology is noteworthy. The roles of AMPA receptors
in the synaptic plasticity, circuit, and behavior have been well elucidated
in rodent, and the importance of AMPA receptors in neuronal function has
been well established. However, the roles of the AMPA receptors in human
cognition and neuronal disease has not been well characterized. To tackle
this huge hurdle, we developed PET probe to visualize AMPA receptors in
human. We detected specific binding signals with high S/N in rodents and
Macaca. Further, we performed first-in human test and obtained potential
specific binding signals in living human brain. We started imaging patients
of various neuronal disorders such as depression, schizophrenia, addiction,
epilepsy, stroke and neurodegenerative diseases.
There are a number of compounds which inhibit or enhance AMPA receptors
function. However, the clinical trials of these compounds have not been
productive. One reason is that these drugs have been tested without examining
the distribution of AMPA receptors. By combining our imaging techniques,
we believe that the success rate of clinical trials will be increased (eg.
AMPA receptors antagonists should be applied to patients with increased
AMPA receptors expression). We hope this approach should break out the
development of novel drugs targeting at AMPA receptors.