Transcript Li Hao - USD Biology

HDAC6 Regulates Glucocorticoid
Receptor Signaling in
Serotonin Pathways with Critical Impact
on Stress Resilience
Julie Espallergues,1* Sarah L. Teegarden,1* Avin Veerakumar,1 Janette Boulden,1 Collin Challis,1 Jeanine Jochems,1
Michael Chan,1 Tess Petersen,1 Evan Deneris,3 Patrick Matthias,4 Chang-Gyu Hahn,1 Irwin Lucki,1 Sheryl G. Beck,2 and
Olivier Berton1
1 Department of Psychiatry, University of Pennsylvania Medical School, and
2 Department of Anesthesiology, Children’s Hospital of Philadelphia Research
Institute and University of Pennsylvania, Philadelphia, Pennsylvania 19104,
3 Department of Neuroscience, School of Medicine, Case Western Reserve
University, Cleveland, Ohio 44106, and
4 Friedrich Miescher Institute for Biomedical Research, CH-4058 Basel, Switzerland
An interesting background paper:
Molecular Adaptations Underlying Susceptibility and Resistance to Social Defeat in Brain Reward Regions
Background
Resistant mice: Social defeat
Upregulated K channels
Rescuing BDNF releasing
Question: How to explain the prolonged depressive behaviors? What is the role of reward
system associated with the social defeat?
Background
Background knowledge about our main paper:
Glucocorticoid Receptor(GR) & Mineralcorticoid receptor(MR)
1. Both bind with cortisol.
2. When they are not bond with hormones, they need chaperone proteins(hsp90, hsp70,
FKBP52) to protect their structure.
3. MR binds when CORT is low(high affinity), can be seen as the threshold for stress responses.
GR binds when CORT is high(low affinity), mediate most of stress behaviors.
Background
Descending limb is associated with MR.
Ascending limb is associated with GR.
Background
In DR, GR activates 5-HT1A
receptor which is inhibitory.
(same in our main paper)
Histone deacetylation and HDAC6 (Histone acetylase 6)
Hsp90 is one of a substrate of HDAC6.
Generally what happens is…
Background
But in our main paper, they were talking about hsp90 as the chaperone protein…
“We show that HDAC6 functions as an Hsp90 deacetylase. Inactivation of HDAC6
leads to Hsp90 hyperacetylation, its dissociation from an essential cochaperone,
p23, and a loss of chaperone activity. In HDAC6-deficient cells, Hsp90-dependent
maturation of the glucocorticoid receptor (GR) is compromised, resulting in GR
defective in ligand binding, nuclear translocation, and transcriptional activation. “
Tso-Pang Yao 2005
Acetylated Hsp90 inhibits the functions of GR.
Background
HDAC6 Regulates Glucocorticoid Receptor Signaling in
Serotonin Pathways with Critical Impact on Stress Resilience
Fig 1 : To make sure there were lots of HDAC6 in raphe
Fig 2: To make sure there were lots of HDAC6 in serotonin neuron
Fig 3:Downregulated HDAC6 expression in the dorsal raphe of resilient and
imipramine-treated mice (social defeat for 10d and imipramine injection for 28d)
Fig 4: Conditional ablation of HDAC6 in raphe neurons
A very interesting method of genetic knockout used in fruit flies ---- Gal4/UAS
Fig 5: Serotonin-selective depletion of HDAC6 promotes an antidepressant-like
phenotype in mice exposed to inescapable stress
Fig 6: Depletion of HDAC6 prevents social defeat-induced hypoexcitability of
serotonin neurons (remember 5-HT1A receptors are inhibitory)
Fig 7: Depletion of HDAC6 prevents social defeat-induced hypertrophy of 5-HT
neurons
Fig 8: HDAC6 depletion leads to Hsp90 hyperacetylation and impaired GR chaperoning
GR agonist
GR inhibitor
GR inhibitor
GR inhibitor
Fig 9: HDAC6 depletion prevents transcriptional and electrophysiological effects of
glucocorticoids in 5-HT neurons
Fig 10: Serotonergic depletion of HDAC6 alters the socioaffective effects of
glucocorticoid hormones
CORT made KO mice hyper-locomotor?
Fig 11: The idea of this paper