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Document Description
Title
KCNQ/M
channels
in the
midbrain
dopaminergic
system
in the
rat
neonatal
hippocampal
lesion
model
of
schizophrenia
Author
Deemyad
,
Tara.
Description
Thesis
(M.Sc.)--Memorial
University
of
Newfoundland
,
2008.
Medicine
Date
2008
Pagination
122 leaves : ill. (some col.)
Subject
Dopaminergic
mechanisms;
Schizophrenia--Etiology;
Subject.MESH
Dopamine
Agents;
Schizophrenia--etiology
Degree
M.Sc.
Degree Grantor
Memorial University of Newfoundland. Faculty of Medicine
Discipline
Medicine
Language
Eng
Notes
Includes
bibliographical
references
(leaves
87-122)
Abstract
Increase
in
dopaminergic
(DA)
neurotransmission
in the
brain
has been
implicated
in
schizophrenia.
One
of the
known
mechanisms
for
promoting
dopamine
release
is
burst
firing
of
DA
cells.
However
,
it
is
unclear
whether
alterations
in
firing
patterns
of
DA
cells
are
associated
with the
disease.
In the
present
study
at
first
I
hypothesized
that
M
current
contributes
to
burst
firing
of
DA
cells
in
slices.
I
therefore
studied
the
effect
of
M
channel
blockade
on the
firing
behavior
of
DA
cells
in the
ventral
tegmental
area.
Then
I
hypothesized
KCNQ
channel
expression
in
VTA
DA
cells
in
nVH
lesion
rats
is
reduced
to
promote
the
excitability
of these
cells.
Therefore
I
examined
the
expression
of
KCNQ3
, a
subunit
that
forms
heterodimeric
channels
with
other
subunits
to
carry
M
currents
with
much
greater
conductance
, in
rats
that
underwent
ventral
hippocampal
lesion
early
in
life
which
has been
widely
used
as a
rat
model
of
schizophrenia.
--
First
, the
effect
of
blocking
M
channels
on the
firing
behavior
was
studies
in
horizontal
brain
slices
that
contained
the
ventral
tegmental
area
using
nystatin
perforated
patch
clamp
recording.
Blocking
the
channel
with
linopirdine
or
XE-991
resulted
in
excitation
of
DA
, but not
GAB
A
cells
in the
ventral
tegmental
area.
This
increase
firing
was
accompanied
by a
reduction
of the
medium
hyperpolarizing
afterpotential
and a
mild
depolarization.
In the
majority
of
DA
cells
tested
,
blocking
these
channels
also
resulted
in
burst
firing.
--
Next
, the
expression
of
KCNQ3
channel
in the
ventral
midbrain
was
studies
in
neonatal
ventral
hippocampal
lesioned
rats.
Bilateral
injection
of
ibotenic
acid
in the
ventral
hippocampus
at
postnatal
7
resulted
in
cell
loss
that was
confirmed
with
Nissl
staining
at the
end
of the
experiment.
The
lesioned
group
had a
gradual
increase
in the
deficit
in
prepulse
inhibition
tested
at
35
,
49
and
56
postnatal
days
, a
hallmark
of this
model.
The
brains
were
processed
immunohistochemically
for the
expression
of
KCNQ3
subunits
in the
midbrain.
I
found
that the
number
of
cells
expressing
KCNQ3
channels
was
decreased
in the
ventral
tegmental
area
of the
lesion
group
as
compared
with the
sham
group.
Double
immunofluorescence
labeling
with
tyrosine
hydroxylase
and
KCNQ3
showed
a
high
percentage
of
colocalization
in
dorsal
tier
of
ventral
tegmental
area
,
suggesting
the
reduction
in
KCNQ3
channel
expression
occurs
in
DA
cells.
In
contrast
, in the
lesion
group
, the
number
of
KCNQ3
positive
cells
was
significantly
increased
in the
red
nucleus
and the
oculomotor
nucleus.
--
In
conclusion
, the
results
in this
thesis
suggest
that
neonatal
hippocampal
lesion
leads
to
decreased
expression
of
KCNQ3
channels
in
DA
cells
that
may
result
in
increased
excitability
and/or
increased
burst
firing
to
enhance
DA
transmission.
This
maybe
one
of the
mechanisms
by
which
the
DA
system
becomes
overactive
in
schizophrenic
brain.
Type
Text
Format
Image/jpeg;
Application/pdf
Source
Paper copy kept in the Centre for Newfoundland Studies, Memorial University Libraries
Local Identifier
a2543056
Rights
The author retains copyright ownership and moral rights in this thesis. Neither the thesis nor substantial extracts from it may be printed or otherwise reproduced without the author's permission.
Collection
Electronic
Theses
and
Dissertations
Scanning Status
Completed
PDF File
(12.07
MB)
--
http://collections.mun.ca/PDFs/theses/Deemyad_Tara.pdf
CONTENTdm file name
135569.cpd
