JAPAN 2015 - Final program AND mini conference

AND (Association of the Study for Neurons and Diseases)
Winter Mini-Conference
-Joint conference with Innovative Area for Micro-endophenotypes of
Psychiatry Disorders –
 Place; K K R A t a m i H o t e l
 Date; J an 2 2nd , 20 1 5
http://www.kkr-atami.gr.jp
Each speaker has 40 min (30-35 min. talk and discussion)
PM 1:00-1:05
Opening remarks by Min Zhuo (University of Toronto)
PM 1:05-1:10
Introduction of Molecular Brain and Molecular Pain by
Bong-Kiun Kaang (Seoul National University)
 Session 1
Chair; Bong-Kiun Kaang (Seoul National University)
PM 1:10-1:50
Graham L. Collingridge (University of Bristol)
Is Alzheimer’s disease caused by LTD gone awry?
PM 1:50-2:30
Fusao Kato (Jikei University School of Medicine)
Pain chronification and amygdala plasticity
 Session 2
Chair; Tsuyoshi Miyakawa (Fujita Health University)
PM 2:45-3:25
Robert Nistico (Sapienza University of Rome)
Synaptic plasticity in multiple sclerosis and in
experimental autoimmune encephalomyelitis
PM 3:25-4:05
Makoto Tominaga (Okazaki Institute for Integrative
Bioscience)
Functional Interaction between TRP channels and anoctamin1
 Session 3
Chair; Satoshi Kida (Tokyo University of Agriculture)
PM 4:20-5:00
Christopher Parsons (Merz Pharmaceuticals GmbH)
Aβ as a target for drug development for
Alzheimer’s disease
PM 5:00-5:40
Yuichi Iino (The University of Tokyo)
Memory formation by axonal transport of an insulin
receptor isoform in Caenorhabditis elegans
PM 5:40-6:20
Min Zhuo (University of Toronto)
Cortical synaptic mechanisms for pleasure and pain
PM 6:20-6:30
Introduction of Molecular Brain review series by
Timothy Bliss
PM 6:30-6:35
Conclusion remarks by Satoshi Kida
PM 7:00-9:00
Reception dinner
Title: Is Alzheimer’s disease caused by LTD gone awry?
Name: Graham L. Collingridge
Affiliation: Centre for Synaptic Plasticity, School of Physiology and Pharmacology,
University of Bristol, U.K
E-mail: glcollingridge@gmail.com
Abstract:
The purpose of our studies has been to identify the signalling cascades that are involved
in N-methyl-D-aspartate (NMDA) receptor-mediated long-term depression (LTD) in the
hippocampus. We wish to use this knowledge to establish how dysregulation of
components of these pathways leads to synaptic injury and cognitive deficits in
neurodegenerative diseases, such as Alzheimer's disease.
Experiments were performed on acute and organotypic hippocampal slices prepared
from juvenile rats. Proteins were targeted pharmacologically and using RNAi.
Working with a variety of collaborators, we have identified the following pathways in
NMDAR-LTD.
GluA2 / NSF / hippocalcin
Akt1 / GSK-3beta / tau
PI3K
JAK2 / STAT3
GIT1 / Arf-1 / PICK1 / Arp2/3
We propose that synaptic injury, an early event in AD, is caused, at least in part, by
dysregulation of NMDAR- LTD. This process is normally involved in physiological
synaptic pruning but in response to a variety of genetic or environmental influences can
prune synapses in an aberrant manner. We propose that a fuller understanding of this
mechanism should lead to better therapeutic strategies.
Title: Pain chronification and amygdala plasticity
Name: Fusao Kato
Affiliation: Department of Neuroscience and Center for Neuroscience of Pain,
Jikei University School of Medicine
E-mail: fusao@jikei.ac.jp
Abstract:
The amygdala is the key structure playing essential roles in linking aversive sensory
information and optimum behavioral outputs that would help the animal better survive.
Of the subnuclei composing the amygdala, the central amygdala (CeA) receives two
kinds of nociception-linked information: directly from the spino-parabrachial pathway
and indirectly from the basolateral amygdala, thus effectively linking nociception and
emotion (Veinante et al, 2013). A recent imaging study in human patients with persistent
pain indicated that the increased spontaneous activity in the emotion-related structures
such as the CeA is the core signature of consolidated chronic pain (Hashmi et al, 2013).
I will present some of our recent findings in the latent chronification process of the
inflammatory pain models observed >6 hours after subcutaneous formalin injection in
rats and mice. The latent consequences included 1) aberrant decrease in nociceptive
threshold in other regions of the body than the site of inflammation (“generalized
sensitization”), 2) synaptic potentiation of LPB-CeA transmission in the right CeA as
confirmed in isolated slices with optogenetic and electrical stimulation of the LPB
afferents in a manner dependent of CGRP, and 3) increased selective uptake of Mn2+ to
the CeA during spontaneous free moving after 6-24 hours post-injection as evidenced
by Mn2+-enhanced MRI with ultra-high magnetic field MRI. The activation of the CeA
by inflammatory/nociceptive information would be a key initiative process for pain
chronification with various outcomes including the aberrantly enhanced nociception “The pain changes the brain and the brain changes the pain”.
Title: Synaptic plasticity in multiple sclerosis and in experimental
autoimmune encephalomyelitis
Name: Robert Nisticò
Affiliation: Department of Physiology and Pharmacology, Sapienza University of
Rome
E-mail: robert.nistico@uniroma1.it
Abstract:
Multiple sclerosis (MS), a neuroinflammatory disorder characterized by demyelination
and progressive axonal loss, is associated with early cognitive deficit, which has a
significant impact on the quality of life of patients. Recent studies highlight the
importance of inflammation-induced synaptic dysfunction in the very early phases of
MS and in a mouse model of MS, the experimental autoimmune encephalomyelitis
(EAE). We have recently shown that in EAE hippocampus long-term potentiation
(LTP) is favored over long-term depression (LTD) in response to repetitive synaptic
activation, through a mechanism dependent on enhanced IL-1β released from
infiltrating lymphocytes or activated microglia. In addition, we have also demonstrated
that platelet-derived growth factor (PDGF) plays a substantial role in favoring both LTP
and brain reserve in MS patients, as this molecule: (1) was reduced in the CSF of
PP-MS patients, (2) enhanced LTP in hippocampal mouse brain slices, (3) was
associated with more pronounced LTP in RR-MS patients, and (4) was associated with
the clinical compensation of new brain lesion formation in RR-MS. Overall these results
suggest that brain plasticity reserve, in the form of LTP, might be crucial to contrast
clinical deterioration in MS. Enhancing PDGF signaling might represent a valuable
treatment option to maintain brain reserve and to attenuate the clinical consequences of
neuronal damage in the progressive phases of MS and possibly in other
neurodegenerative disorders.
Title: Functional Interaction between TRP channels and anoctamin1
Name: Makoto TOMINAGA
Affiliation: Division of Cell Signaling, Okazaki Institute for Integrative Bioscience
E-mail: tominaga@nips.ac.jp
Abstract:
Transient receptor potential (TRP) channels are nonselective cation channels with high
Ca2+ permeability. We found physical and functional interaction between TRP
vanilloid 4 (TRPV4) and anoctamin1 (ANO1), a Ca2+-activated chloride channel, in
HEK293T cells and choroid plexus epithelial cells (CPECs). Chloride currents
induced by a TRPV4 activator were markedly increased in an extracellular
calcium-dependent manner in HEK293T cells expressing TRPV4 with ANO1 and in
CPECs. We also found physical interaction between TRPV4 and ANO1 in both cell
types. Cell volume changes were induced by ANO1-mediated chloride currents in
parallel with membrane potential changes, and the cell volume was significantly
decreased at negative membrane potentials by TRPV4-induced ANO1 activation.
These physical and functional interactions between TRPV4 and ANO1 can modulate
water transport in the choroid plexus. Next, we found similar physical and functional
interaction between TRPV1 and ANO1 in HEK293T cells and mouse sensory neurons.
Capsaicin-evoked inward currents were significantly inhibited by a specific ANO1
antagonist T16Ainh-A01 (A01) in mouse DRG neurons. In addition, capsaicin-evoked
action potential was drastically inhibited by A01. Furthermore, pain-related behaviors
in mice treated with capsaicin were significantly reduced by the concomitant
administration of A01. These results indicate that the TRPV1-ANO1 interaction is a
significant pain-enhancing mechanism in the peripheral nervous system. Thus, TRP
channel/anoctamin complex could play many important roles in various tissues.
Title: Aβ as a target for drug development for Alzheimer´s disease
Name: Christopher G. Parsons
Affiliation: Principal Scientific Expert – Pharmacology, Non-Clinical Science,
Merz Pharmaceuticals GmbH, Eckenheimer Landstr. 100, D-60318 Frankfurt am
Main, Germany
E-mail: christopher.parsons@merz.de
Abstract:
β-amyloid (Aβ) is widely accepted to be one of the major pathomechanisms underlying
Alzheimer's disease (AD), although there is presently lively debate regarding the
relative roles of particular species / forms of this peptide [1]. Most recent evidence
indicates that soluble oligomers rather than plaques are the major cause of synaptic
dysfunction and ultimately neurodegeneration in AD [2]. Soluble oligomeric Aβ has
been shown to interact with several synaptic proteins, for example NMDA / mGluR5
glutamatergic receptors, postsynaptic anchoring proteins and uptake / release
transporters responsible for maintaining glutamate homeostasis. Indeed both NMDA
receptor antagonists such as memantine and Ro 25-6981 as well as the mGluR5
negative allosteric modulator MPEP are able to reverse oligomeric Aβ induced deficits
in synaptic plasticity such as long term potentiation (LTP) [3].
Molecules that disrupt assembly of soluble Aβ oligomers or interfere with their binding
to neuronal receptors represent a promising alternative approach for the treatment and
possible prevention of AD. In our hands three classes of Aβ aggregation modulators,
scyllo-inositol (AZD-103), the 8-hydroxyquinoline PBT2 and the dipeptide
NH2-D-Trp-Aib-OH were also able to reverse such oligomeric Aβ induced synaptic
deficits in LTP [4].
There is even considerable debate which particular Aβ oligomeric species are the most
synaptotoxic with some champions of e.g. dodecameric assemblies (Aβ*56) whilst
others claim that trimers and even dimers of Aβ are the most relevant pathogen in AD.
This prompted us to look for molecules that interfere with Aβ oligomerization at its
earliest step as potential disease modifying agents in AD.
Identification of novel molecules that block Aβ assembly is performed at Merz using a
proprietary Aβ oligomer specific, TR-FRET-based screen using Aβ1-42 at a low
concentration of 200 nM. Hits are validated using a cell-based high content screen
(HCS) that detects binding of patho-physiologically relevant concentrations (1-50 nM)
of soluble oligomeric Aβ to hippocampal neuronal synapses. Validated hits are then
tested for functional effects such as reversal of low nM Aβ oligomer-induced deficits in
LTP in vitro [4] and then in vivo.
Use of these TR-FRET and HCS assays has proven this screening platform to be very
well suited for the identification of novel CNS drug-like Aβ assembly blockers. The
knowledge acquired on the structural requirements for Aβ oligomer assembly inhibition
was then applied to develop in silico (pharmacophore) models. These compound-based
models were used to virtually screen large vendor compound libraries for new chemical
entities with Aβ aggregation inhibitory properties.
[1] “Molecular mechanisms of neurodegeneration in Alzheimer’s disease” Crews L and
Masliah E; Hum Mol Genet. 2010 (19) R12-20
[2] “Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and
behavior” Selkoe DJ; Behav Brain Res. 2008 (192) 106-113
[3] “Therapeutic significance of NR2B-containing NMDA receptors and mGluR5
metabotropic glutamate receptors in mediating the synaptotoxic effects of β-amyloid
oligomers on long-term potentiation (LTP) in murine hippocampal slices” Rammes G,
Hasenjäger A, Sroka-Saidi K, Deussing JM, Parsons CG; Neuropharmacology 2011
(60) 982-990
[4] “Aggregation inhibitors reverse ß-amyloid induced inhibition of long term
potentiation (LTP) in murine hippocampal slices” Rammes G, Hasenjäger A,
Sroka-Saidi K, Parsons CG; Contribution to SfN’s 41st annual meeting. Washington DC,
November 2011.
Title: Memory formation by axonal transport of an insulin receptor isoform
in Caenorhabditis elegans
Name: Yuichi IINO
Affiliation: Department of Biological Sciences, Graduate School of Science, The
University of Tokyo
E-mail: iino@bs.s.u-tokyo.ac.jp
Abstract:
Insulin signaling plays conserved roles for representing feeding status in various
animals. In addition, mammalian insulin signaling is suggested to be involved in
learning and memory, but the precise mechanisms have been unclear. We have
previously found that the insulin/PI 3-kinase pathway is essential for
starvation-dependent learning called taste avoidance learning in C. elegans. While C.
elegans fed under the presence of salt (NaCl) shows preference for salt, they learn to
avoid salt by starvation in the presence of salt. We have previously found that the
insulin/PI-3 kinase pathway in the sensory neuron is essential for the taste avoidance
learning. Now we find that there are two major isoforms of the insulin receptor DAF-2,
DAF-2a and DAF-2c, of which only DAF-2c can support learning. Interestingly,
DAF-2c is preferentially localized to the synapse-rich axonal region, especially under
starved conditions, and this localization is essential for its function in salt avoidance
learning. Activation of PI 3-kinase pathway in the axonal region, but not elsewhere in
the sensory neuron, using a photo-activatable probe, causes salt avoidance behavior in
well-fed animals, suggesting that the localization of the receptor is a key for the
formation of starvation memory. The C. elegans homologue of calsyntenin, a
transmembrane protein implicated in Alzheimer's disease, acts as a cargo adaptor for
axonal transport of DAF-2c.
Title: Cortical synaptic mechanisms for pleasure and pain
Name: Min Zhuo
Affiliation: Department of Physiology, Faculty of Medicine, University of Toronto
E-mail: min.zhuo@utoronto.ca
Abstract:
Pleasure and pain are two major forms of emotion that affect our daily life. Both human
beings and animals seek the pleasure, and try to avoid any potential dangerous or
painful stimuli or environment. Recent human imaging and animal studies suggest
that cortical regions such as the anterior cingulate cortex (ACC) and insular cortex (IC)
play important roles in the process of positive (pleasure) and negative (pain) emotion.
In this review, I will discuss some of recent progress, and explore possible synaptic
mechanisms that mediate pain and pleasure in the cortex.