HDAC6-mediated effects in mouse models of stress and depression

Recent preclinical studies indicate that loss of HDAC6 function promotes stress resilience and induces antidepressant-like responses in rodents. Although these results point to HDAC6 inhibition as a potential mechanism for the treatment of neuropsychiatric conditions, in vivo pharmacological target validation has been hampered by lack of isoform selectivity and poor brain bioavailability of current probes. Additionally, as more targets of HDAC6 are found, the downstream mechanisms that mediate this activity remain poorly understood. This work validates the behavioral activity of two novel pyrimidine hydroxyl amide small molecules with high selectivity for HDAC6 and improved brain bioavailability in a number of mouse models of stress and depression and explores some potential downstream mechanisms. Data here shows that ACY-738 and ACY-775 led to anxiolytic effects in the open-field, marble burying and novelty induced hypophagia tests, and antidepressant-like effects in tail suspension test and following chronic social defeat stress. Hsp90, a known substrate of HDAC6, plays a key role in stress regulation through its function as a chaperone of the glucocorticoid receptor (GR) and its acetylation status regulates downstream hormone signaling via GR, but the contribution of this molecular mechanism in stress homeostasis has not been clearly elucidated. This study shows that acetylation of Hsp90 is differentially regulated in mice that are spontaneously resilient to developing a depressive-like phenotype and this led to differences in association with GR and other co-chaperones, and alters GR trafficking into the nucleus. Additionally, the direct contribution of this acetylation is investigated using viral-mediated expression of acetylation mimic mutant of Hsp90 in the serotonin system. Overexpression of this acetyl mimic leads to an antidepressant-like phenotype compared to mice expressing control virus and has similar effects to HDAC6 loss of function on GR chaperone complex and trafficking. This work also begins to explore the effects of HDAC6 loss of function on the neuroplastic effects that could be related to its antidepressant-like effect. The results presented here validate new isoform-selective probes for pharmacological inhibition of HDAC6 in the CNS, highlight the likely involvement of Hsp90 hyperacetylation in the antidepressant response to HDAC6 inhibition, and serve as proof of principle that HDAC6 could be a valid target for antidepressant development