Depression

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Depression

• An affective disorder
• affect means emotional state or mood

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• http//www.youtube.com/watch?vJhlWddAXSRA

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Nature 455894 2008
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• Treated by
• Electroconvulsive shock
• Psychotherapy
• Antidepressants

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Animal models of depression
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Deep brain stimulation of the Nucleus accumbens
or the subgenual cingulate cortex decreases
depression
This is thought to inhibit the activity of these
areas
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BDNF is a neurotrophic factor that promotes
neurogenesis, growth of axon branches and
dendrites, and synaptogenesis
Depression is associated with increased BDNF in N
accumbens and VTA
The Amygdala processes emotionally stressful
stimuli
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Stress (and depression) lowers BDNF in the
hippocampus
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Postmortem data from depressed humans
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A human polymorphism in the pro-domain of the
BDNF gene affects the packaging and release of
BDNF has different effects on different aspects
of depression
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• Monoamine Hypothesis Depression results from a
  deficit in one or both of the serotonin and
  norepinephrine diffuse modulatory systems.

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Serotonin and Norepinephrine modulatory systems
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• Alternative diathesis-stress hypothesis
• Diathesis means a predisposition to a disease
• Activation of glucocorticoid receptors in the
  hippocampus downregulates the hypothalamic
  pituitary adrenal system.
• A lot of maternal care in rats upregulates
  glucocorticoid receptors in hippocampus

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• There is evidence that neurogenesis in the
  hippocampus is important for mood regulation.
• Stress-induced depression down-regulates BDNF
  (brain-derived neurotropic factor) expression and
  hence down regulates neurogenesis.
• Antidepressants (imipramine) upregulateBDNF
  expression

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Stress-induced dimethylation of chromatin
surrounding BDNF promoter decreases expression.
Antidepressant-induced acetylation upregulates
expression.
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5-HT1b receptors and depression
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• 5-HT1b receptors are typically located on the
  presynaptic terminals of either serotonergic or
  other neurons.
• Activation of 5-HT1b receptors decreases release
  of 5-HT.

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• P11 interacts with 5-HT1b, but not other 5-HT or
  Dopamine receptors in a yeast two-hibrid assay

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• Fig. 1. Identification of an interaction between
  5-HT1B receptors and p11. (A) Results from a
  yeast two-hybrid screen showing an interaction of
  p11 with the 5-HT1B receptor (left blue color),
  but not with an unrelated bait (C 115 right no
  color), or with pRP21, 5-HT1A, 5-HT2A, 5-HT5A,
  5-HT6, D1, or D2 receptors. (B)
  Coimmunoprecipitation confirming that p11
  interacts with (left panel) V5 epitopetagged
  5-HT1B receptors in HeLa cells and with (right
  panel) native 5-HT1B receptors in brain tissue
  from wild-type, but not p11 KO, mice. The
  immunoprecipitates were analyzed by Western
  blotting using a p11-specific antibody. The
  nonspecific band corresponds to the light chains
  of the antibodies against V5 or 5-HT1B receptors
  ( -V5 and -5HT1B). (C) Immunofluorescence
  staining of p11 (left, red fluorescence), V5
  epitopetagged 5-HT1B receptors (middle, green
  fluorescence) and their colocalization (right,
  yellow fluorescence) at the cell surface in HeLa
  cells. (D) In situ hybridization made on coronal
  sections from a rat brain showing that the
  distribution of p11 mRNA is similartothatof5-HT1B
  receptor mRNA in (left to right) frontal cortex,
  ventromedial hypothalamus (arrow), hippocampus
  (arrow), and raphe nuclei (arrow).

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• Coimmunoprecipitation shows that P11 interacts
  with V5-tagged 5-HT1b receptors in HeLa cells and
  in wildtype Mouse brain (but not P11 knock-out
  brain).

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• Immunocytochemical Colocalization of P11 and
  5-HT1b receptors in HeLa cells

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• In situ hybridization showing similar
  distribution of P11 and 5-HT1b mRNAs

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Raphe Nuclei
Hippocampus
Ventromedial hypothalamus
Frontal cortex
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• Regulation of P11 expression by antidepressant
  treatments and in depression like states.

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The tricyclic antidepressant imipramine or
electroconvulsive shock upregulate P11 mRNA
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• P11 mRNA was down-regulated in depressed mice
  and human brains

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Non-helpless mouse
Helpless Mouse
Human
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• Fig. 2. Regulation of p11 expression by
  antidepressant treatments and in depression-like
  states. In situ hybridization illustrating an
  up-regulation of p11 mRNA in the forebrain
  following (A) repeated treatment with imipramine
  10 mg/kg per day, intraperitoneally (i.p.) for
  14 days in mice (n 8 per group) and (B)
  electroconvulsive therapy (ECT) for 10 days in
  rats (n 5 per group). Conversely, p11 mRNA was
  down-regulated in (C) the forebrain in helpless
  H/Rouen versus nonhelpless NH/Rouen mice (n 10
  per group) and (D) in patients who suffered from
  unipolar major depression (n 15 per group).
  Data from the anterior (A B C, left D) and
  posterior (C, right) cingulate cortices were
  normalized to the corresponding controls and
  represent means SEM. P lt 0.05, P lt 0.001
  versus control by Student's t test.

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• Over expression of P11 in Cos-7 cells increases
  the amount of 5-HT1b at the cell surface

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• Coexpression of P11 with 5-HT1b receptor enhanced
  the ability of serotonin to counteract the
  activation of adenyl cyclase by forskolin

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• Mice overexpressing P11 showed behavioral changes
  similar to antidepressant treatments reduced
  thigmotaxis or immobility in a tail suspension
  test.

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• P11 knockouts have depression-like behavioral
  phenotypes
• Increased thigmotaxis and tail-suspension induced
  immobility

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• Fig. 3. Biochemical and behavioral effects of
  overexpression of p11 in cells and in transgenic
  mice. (A) Biotinylation experiment from COS-7
  cells showing that p11 increases the amount of
  5-HT1B receptors at the cell surface. Data were
  normalized to the amount in cells transfected
  only with 5-HT1B receptors and represent means
  SEM for three experiments, each in triplicate.
  (B) The ability of serotonin (10 µM) to
  counteract forskolin-induced cAMP formation in
  COS-7 cells transfected with the 5-HT1B receptor
  is increased in the presence of cotransfected
  p11. There was no significant difference in the
  cAMP responses to forskolin with or without p11.
  Data are normalized to forskolin-stimulated
  conditions, with or without p11, and represent
  means SEM. Behavioral analysis on (C)
  thigmotaxis and (D) the tail suspension test in
  transgenic mice overexpressing p11 under the
  CamKII promoter. Black bars indicate mice with no
  treatment and white bars doxycycline-treated
  mice. Data represent means SEM for 10 to 18
  mice per group. P lt 0.05, P lt 0.01 versus
  respective control by Student's t test.

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P11 knockout results in less binding by 5-HT1b
ligands

• 5ht1b antagonist binding
• Goes down

P11KO reduces ability of 5HT to down regulate a
kinase
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• P11 knockouts caused a loss of ability of 5-HT
  and the 5-HT1b agonist, anpirtoline to
  downregulate ERK1/2 (Fig 4c) or to decrease a PKA
  site phosphorylation (Fig 4D)

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• 5-HT acting on 5-HT1b recptors in terminals of
  cortical glutamatergic neurons in the striatum
  reduced PSP amplitude in wildtype, but very
  little in P11 knock-outs

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• Since 5-HT1b receptors decrease 5-HT turnover and
  P11 increases this decrease, P11 knockouts
  increase this 5-HT turnover (Fig 4F)

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But 5-HT1b antagonist decreases ultrasonic
vocalization in the rat
Dawson et al O6