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 Berton11 Department of Psychiatry, University of Pennsylvania Medical School, and

2 Department of Anesthesiology, Children’s Hospital of Philadelphia ResearchInstitute and University of Pennsylvania, Philadelphia, Pennsylvania 19104,3 Department of Neuroscience, School of Medicine, Case Western Reserve

University, Cleveland, Ohio 44106, and4 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.

In DR, GR activates 5-HT1A receptor which is inhibitory. (same in our main paper)

Background

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 inSerotonin 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 andimipramine-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