Field: Neuroscience/Medicine
Session Topic:
Molecular basis of human mind and mental disorders
Speaker:
Wataru Ukai, Sapporo Medical University
Title: The Approach of Reconstruction for Damaged Neural Network in Neuropsychiatric
Disorders
Neural stem cells (NSCs) have recently been identified in mammalian brains,
including human. The long-standing dogma of “no new neuron” was overturned by the
discovery of NSCs in the adult brain. NSCs are primordial and uncommitted cells with
two characteristic properties; self-renewal and multipotency. NSCs give rise to various
types of cells in the central nervous system including neurons, astrocytes and
oligodendrocytes. NSCs attract interests of a large number of researchers in various
scientific fields because of their possibility of becoming innovative therapeutic strategy
for neurodegenerative disorders previously considered untreatable. Recently, many
researchers have hypothesized that not only neurological disorders, but also psychiatric
disorders, such as depression, might also be related to the disturbance of NSC functions.
In the study of depression, we examined the influences of antidepressants and mood
stabilizers on the proliferation and differentiation activity of NSCs, and survival
potential of neurons. Antidepressants and mood stabilizers promoted neuronal
differentiation of NSCs at concentrations similar to their clinical usage. The
antidepressants increased secretion of BDNF from the NSC. Mood stabilizers promoted
survival of NSCs, while antidepressants showed no significant effect. We hypothesize
that the different potential of NSC differentiation by antidepressants and mood
stabilizers relate to their differences of clinical response.
Several latest studies have indicated that NSCs may play a significant role in the
pathophysiology of alcohol related disorders. Although ethanol has been known to cause
loss of cells and consequent morphological changes in nervous system, it is likely that
ethanol exerts these cytotoxic effects through inhibition of neurogenesis. In the previous
study, we have indicated the action of ethanol on NSC differentiation. Ethanol inhibited
NSC differentiation to neurons at lower than 100 mM. In contrast, same concentrations
of ethanol increased their differentiation to glias. In addition, we have also indicated that
ethanol reduced BDNF production and BDNF recovered the ethanol induced reduction of
neuronal differentiation. It is suggested that the trophic factor signaling change may
involved in these effects. However, precise cellular mechanism of NSC function change is
not clear. So, we analyze the effect of ethanol on NSC function by focusing or using, (1)
transcriptional function change, (2) neurogenesis promoting drugs, (3) NSC marking in
the brain.
Firstly, we tried to analyze the effect of ethanol on the important transcriptional
repressor, NRSF/REST, which is known to regulate neural gene expression negatively in
the neuronal cells. Recently it is indicated that NRSF/REST is the important factor for
the decision of NSC differentiation to neurons or glias. We measured DNA binding
activity change of NRSF by the method of DNA binding ELISA. Ethanol enhanced the
binding activity of NRSF. The NRSF expression was increased by the treatment of
ethanol. We have indicated the reduction of MEK/ERK signaling by ethanol in NSC,
which is known as an important molecule on the trophic factor signaling. So, we next
analyze the implication of MEK/ERK signaling on the NRSF function change. MEK
inhibitor U0126 inhibited neuronal differentiation, and potentiated DNA binding activity
of NRSF. These results suggest ethanol inhibit NSC differentiation to neurons possibly
through reducing MEK/ERK signaling followed by the activation of NRSF.
In the analysis of ethanol action on NSC function, secondly we focused on the
neurogenesis promoting drugs. We have indicated that antidepressant treatment
promoted neuronal differentiation. So, we investigated the effect of antidepressant on the
ethanol inhibition of NSC differentiation. Antidepressant could have potential to recover
ethanol inhibition. How does antidepressant suppress ethanol action? We focused on ER
function change. Because recent evidences suggest the important role of ER function on
neuronal survival and neurogenesis, ER function impairment in neuronal development
and survival is also considered as a key mechanism in the pathopsysiology of
neuropsychiatric disorders. In this study, ER stressor thapsigargin inhibited NSC
differentiation to neurons in the concentrations those did not affect NSC survival.
Antidepressants treatment suppressed ER stress induced inhibition of NSC
differentiation, and ER stress response protein reduction is involved in the action of
antidepressants. Next we analyzed the effect of ethanol on ER function of NSCs. In the
analysis of ER-stress response molecule change, we could detect increae of
phospholylated PERK by ethanol which indicate the ER function change by ethanol. Then
we analyzed the influence of ER function change on NRSF activity. Thapsigargin
exposure increase GRP78 expression and also increased NRSF expression in the same
concentration. And thapsigargin reduced MEK/ERK signlaling as seen by ethanol. So, we
hypothesized that ER Function change might be involved in the mechanism of NRSF
activation by ethanol
Finally, we will show the beginning data about analysis using marked NSC in the
brain by intravenous transplantation method. To analyze the effect of ethanol on neural
network formation and repair in vivo, we used the NSCs transplantation into the fetal
alcohol syndrome (FAS) model rat. We could detect labelled NSCs in the various areas in
the brain, especially cingulate cortex, subventricular zone and hippocampus. The number
of migrated NSCs in FAS group was larger than control group suggested the effective
migration of transplanted NSCs in the impairment neural network in the FAS model rat.
The data of behavioral change will be shown.
Ethanol can affect neural network formation by changing NSC function especially in the
process of differentiation. It could determine that ethanol-induced changing NRSF
activity through altered MEK/ERK signaling and ER function underlies the mechanism
of NSC function change. It is suggested that the intravenous NSC transplantation can be
a useful method to clarify the neural network reconstruction mechanism damaged by
ethanol and the other neuropsychiatric disorders.