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10F125
O-07
Neuregulinβ1 enhances expression of nicotinic acetylcholine receptors via
PI3K/MAPK pathways in the major pelvic ganglion neurons
Han-Gyu Kim, Choong-Ku Lee and Seong-Woo Jeong
Department of Physiology, Yonsei University Wonju College of Medicine,
Republic of Korea
Neuregulin (Nrg) is a growth factor which binds to the ErbB family of receptor
tyrosine kinase and is expressed in the central and peripheral neurons to
regulate various functions including development, cell survival, and gene
expression. Among different products of the Nrg genes, Nrg1 is known to
contain acetylcholine receptor inducing activity (so called ARIA) and thus
regulate expression of nicotinic acetylcholine receptor (nAchR) at central
synapse and neuromuscular junctions. Here, we tested whether Nrg1 signaling
regulates expression of nAchR in autonomic major pelvic ganglion (MPG)
containing both sympathetic and parasympathetic neurons. First of all,
conventional RT-PCR analysis revealed that MPG neurons endogenously
express Nrg1 comprising Type I and Type III, and ErbB2/ErbB3 with lack of
ErbB4. When the MPG neurons were incubated with NRG1-β1 (5 nM) for 6 hr in
culture after dissociation, the nAchR α3 and β4 subunits were 1.7-fold
increased as revealed by real-time PCR and Western blotting analyses.
Consistent with the molecular data, patch-clamp studies showed that NRG1-β1
significantly enhanced nAchR currents in both types of the MPG neurons. In
contrast, NRG1-β1 failed to alter voltage-gated T- and N-type calcium
currents. Unlike NRG1-β1, other trophic factors (NRG1-α1, NGF and CNTF)
had no effects on nAchR currents. NRG1-β1-induced increase in nAchR
currents was blocked by AG825, an ErbB2 inhibitor, LY294002 and wortmanin,
specific inhibitors of PI3K, and U0126, a specific inhibitor of MEK1/2 kinases.
Taken together, these data suggest that Nrg1-β1 up-regulates nAchR via PI3K
and MAPK signalling pathways in the autonomic MPG neurons and thus may
play a role in regulation of excitatory synaptic transmission. This study was
supported by a grant of Myung-Sun Kim Memorial Foundation (2008).
Key Word : Neuregulin, nAchR, PI3K, MAPK
저자 : 김한규, 이충구, 정성우
소속 : 연세대학교 원주의과대학 생리학 교실
10F155
O-08
Lobule-specific membrane excitability of cerebellar Purkinje cells
Chang-Hee Kim, Jun Kim, Sang Jeong Kim
Department of Physiology, College of Medicine, Seoul National University
Cerebellum underlies the control of posture and balance, fine coordination of
motor movement, and working memory. Cerebellar Purkinje cells (PCs) are key
to a variety of motor- and learning-related behavior by integrating multimodal
afferent inputs and taking up the sole output of the cerebellar cortex. PCs are
known to generate high-frequency action potentials. The pattern and rate of
firing are under the control of both synaptic input and intrinsic ion channels that
allow the neurons to fire spontaneously in the absence of synaptic input.
Intrinsic membrane excitability determines the input-output relationship of
neurons and therefore governs the functions of neural circuits. Cerebellar
vermis consists of ten lobules (lobule I-X), and each lobule has different
function. However, lobule-specific difference of electrophysiological properties
of PC is incompletely understood. To address this problem we performed a
systematic study of PC spiking patterns from different lobes (lobules III, IV, V
vs. X). Using patch clamp technique, passive and active properties of PC were
evaluated in slices prepared from rats (P22-24). Two types of firing patterns
were identified in response to depolarizing current injections in PCs of lobules
III, IV, and V; Tonic-firing showing Na+ spikes at regular intervals throughout
the current pulse (71.4%), and Complex-bursting showing both Na+ spikes and
Ca2+-Na+ spikes (28.6%). In contrast PCs in vestibulocerebellum (lobule X)
exhibited four types of firing patterns; Tonic-firing (37.9%), Complex-bursting
(6.9%), delayed-firing showing a delayed onset of firing in response to current
injections (27.6%), and initial bursting showing short firing of a few action
potentials (27.6%). This difference in firing patterns probably contributes to
lobule-specific processing of input-output relationship.
Key Word : Purkinje cell, intrinsic excitability, firing pattern, vestibulocerebellum,
patch-clamp
저자 : 김창희, 김전, 김상정
소속 : Department of Physiology, College of Medicine, Seoul National University
10F157
O-09
Spinal GRPR neurons mediate nerve injury-induced pain as well as itch in
rodents
Chengjin Li, Seung Keun Back, Jaehee Lee, Suk K. Baek, Heung Sik Na
Neuroscience Research Institute and Department of Physiology, Korea University
College of Medicine, 126-1 Anam-dong 5 Ga, Sungbuk-Gu, Seoul, 136-705,
Korea
Gastrin-releasing peptide receptor (GRPR) has been suggested as an itchspecific gene in the spinal cord (Sun et al., Nature, 2009). They described that
selective ablation of GRPR-expressing lamina I neurons led to deficits in itchrelated scratching behaviors without any effects on pain behaviors including
nerve injury-induced mechanical allodynia. It has been known that two types of
mechanical allodynia, such as static and dynamic allodynia, can be detectable
in neuropathic patients, and may be mediated by distinct mechanisms. In the
present study, we investigated the role of spinal GRPR in each of static and
dynamic allodynia using both rat- and mouse-tail models of neuropathic pain.
Bombesin-saporin (bombesin-sap) was administered intrathecally to ablate
spinal GRPR-expressing neurons. Scratching behaviors evoked by pruritogenic
agents, such as serotonin and chloroquine, and physiological pain behaviors
were analyzed before nerve injury. Static or dynamic allodynia was assessed by
the application of von Frey filaments to the tail or brushing the tail with a
filament, respectively. RC3095, a GRPR antagonist, was given intrathecally to
see its effects on static and dynamic allodynia in neuropathic rats. Bombesinsap treatment resulted in reduction of GRPR-immunoreactive cells in lamina I
of spinal dorsal horn and scratching deficits. Physiological pain behaviors of
these animals were not different from those of control animals. Following the
partial injury of tail-innervating nerves, animals treated with bombesin-sap
exhibited comparable dynamic allodynia to control one. However, they failed to
manifest static allodynia during the entire experimental period. In addition,
RC3095 relieved static, but not dynamic, allodynia. These findings suggest that
spinal GRPR mediates nerve injury-induced static mechanical allodynia as well
as itching sensation in normal state.
Key Word : GRPR, Itch, Neuropathic pain, Static allodynia, Dynamic allodynia
저자 : 이성금,백승근,이재희,백숙경,나흥식
소속 : 교려대학교 의과대학 생리학교실
10F134
O-10
A Change of Synaptic Plasticity in Local Neural Circuit of Insular Cortex and
Hippocampus Following Unilateral Deafferentation of Vestibular System in Rats
Gyoung Wan Lee2, Kwang Hyun Ryoo1, Min Sun Kim1, Myung Yae Choi1 ,
Byung Rim Park1
1Department of Physiology, Wonkwang University School of Medicine and
Vestibulocochlear Research Center, Iksan, 570-749, Korea 2Department of
Nursing, Wonkwang Health Science College, Iksan, 570-749, Korea
The vestibular afferent information about posture arising from the vestibular
end-organs in the inner ear reaches either cortex or hippocampal formation
that processes the spatial memory. The aim of present study was to observe
temporal changes of the long-term potentiation (LTP), a synaptic model of
memory, in local neural circuits of the cortex and hippocampus following
unilateral labyrinthectomy (UL). The field excitatory postsynaptic potential
(fEPSP) was recorded using 64 multi-extracellular recording system in the layer
4 of cortical slice and CA1 field of hippocampal slices removed from rats at 24
hours, 1 week, and 1 month following surgical UL. Theta burst stimulation
applied to the local neural circuits of insular cortical or hippocampal slices to
elicit the induction of LTP. Compared with sham animals, there was a
significant suppression of LTP induction in the hippocampal slice at 24 hours
after UL. Especially, the suppression of LTP induction was more prominent on
the contralateral than ipsilateral side of the hippocampus to UL. The degree of
LTP induction was similar with dose of control animals at 1 week and 1 month
following UL. On the contrary, there was minimal changes of LTP at 24 hours
but marked reduction of LTP induction 1 weeks after UL compared with sham
animals. Asymmetry of LTP induction at bilateral insular cortex was noted 1
month after UL. These data suggest that the synaptic plasticity at synaptic level
in the hippocampus and insular cortex is significantly affected in course of
vestibular compensation following unilateral dysfunction of the vestibular endorgans.
Key Word : Hippocampus, Insular cortex, Long-term potentiation, Vestibular
system, Labyrinthectomy
저자 : 이경완 2, 류형광 1, 김민선 1, 최명애 1, 박병림 1
소속 : 원광대학교 의과대학 생리학교실
10F099
O-11
Nox2-derived ROS in spinal cord microglia contribute to peripheral nerve injuryinduced neuropathic pain
Donghoon Kim¹, Byunghyun You¹, Eun-Kyeong Jo², Sang-Kyou Han³, Melvin I.
Simon³, and Sung Joong Lee¹
¹Department of Oral Physiology, School of Dentistry, Seoul National University,
Seoul, Republic of Korea. ²Department of Microbiology and Infection Signaling
Network Research Center, College of Medicine, Chungnam National University,
Daejeon, Republic of Korea. ³Department of Pharmacology, University of
California at San Diego, La Jolla, CA, 92093, U.S.A.
Increasing evidence supports the notion that spinal cord microglia activation
plays a causal role in the development of neuropathic pain after peripheral
nerve injury, yet the mechanisms for microglia activation remain elusive. Here,
we provide evidence that NADPH oxidase 2 (Nox2)-derived ROS production
plays a critical role in nerve injury-induced spinal cord microglia activation and
subsequent pain hypersensitivity. Nox2 expression was induced in dorsal horn
microglia immediately after L5 spinal nerve transection (SNT). Studies using
Nox2-deficient mice show that Nox2 is required for SNT-induced ROS
generation, microglia activation, and proinflammatory cytokine expression in
the spinal cord. SNT-induced mechanical allodynia and thermal hyperalgesia
were similarly attenuated in Nox2-deficient mice. In addition, reducing
microglial ROS level via intrathecal sulforaphane administration attenuated
mechanical allodynia and thermal hyperalgesia in SNT-injured mice.
Sulforaphane also inhibited SNT-induced proinflammatory gene expression in
microglia and studies using primary microglia indicate that ROS generation is
required for proinflammatory gene expression in microglia. These studies
delineate a pathway involving nerve damage leading to microglial Nox2generated ROS resulting in the expression of proinflammatory cytokines that
are involved in the initiation of central sensitization and neuropathic pain.
Key Word : microglia, NADPH oxidase, ROS, cytokine, sulforaphane
저자 : 김동훈¹, 유병현¹, 조은경², 한상규³, Melvin I. Simon³, 이성중¹
소속 : 서울대학교 치의학대학원 생리학교실
10F149
O-12
Role of Jak3 in the neuronal precursor cell Survival and differentiation through
the Regulation of Bcl Expression.
Yun Hee Kim¹², Yi-Sook Jung¹, Soo Hwan Lee¹, Chang-Hyun Moon¹, Hyun Goo
Woo¹ and Eun Joo Baik¹²
Departments of ¹Physiology, and ²Chronic Inflammatory Disease Research
Center, Ajou University School of Medicine, Suwon, 442-749, KOREA.
Neuronal precursor cells (NPCs) can survive, proliferate and differentiate into
neurons and astrocytes in growth factor (GF)-rich condition including
epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF).
Withdrawal of these GFs induced apoptotic cell death. Although Jak3 inhibition
might be associated with cell differentiation, the role of JAK3 on neuronal
survival is not elucidated. Mouse embryo NPCs were obtained from E13 mice
and cultured in DMEM media without GFs. In GF-depleted condition, NPCs
died as apoptotic death. Here, we examined whether Jak3 inhibition protect
GF-depleted cell death. The Jak3 inhibitors (1-10 uM) including WHIP154,
WHIP131 and WHIP97 notably protected the NPCs in serum-depleted condition
and even in DMEM condition. However, WHIP258, a negative control did not
showed the survival effect. The survived NPCs maintained a prominent
proliferative capacity for more than 5 days. Interestingly, BrdU, Ki67 and
Nestin(+) cells survived in the GF deprivation media and also the NPCs
differentiated into neurons and astrocytes. Jak3 inhibitors, but not Jak2 inhibitor
AG490, increased the adhesion molecule expression such as L1, N-cadherin
and NCAM. GF deprivation increased the expression of Bcl-xL/S which is a
dominant inhibitor of Bcl-2, an anti-apoptosis factor. Jak3 inhibitor suppressed
the expression of Bcl-xL/S. In conclusions, Jak3 inhibition plays a potent
protective role against GF-depleted apoptotic NPC death. Acknowledgements:
This study was supported by the Korea Science and Engineering Foundation
through the Chronic Inflammatory Disease Research Center (R13-2003-019).
Key Word : Neurogenesis, neuronal precursor cell, apoptosis, Jak3
저자 : 김윤희¹²,정이숙¹,이수환¹,문창현¹, 우현구¹, 백은주¹²
소속 : 아주대학교 의과대학 생리학교실