BEGIN:VCALENDAR
VERSION:2.0
PRODID:-//Talks.cam//talks.cam.ac.uk//
X-WR-CALNAME:Talks.cam
BEGIN:VEVENT
SUMMARY:Circuit-guided identification of novel GPCR-based antidepressants 
  - Dr Hermany Munguba
DTSTART:20231005T123000Z
DTEND:20231005T133000Z
UID:TALK206734@talks.cam.ac.uk
CONTACT:Christian Wood
DESCRIPTION:Psychiatric diseases are driven by dysregulation at the molecu
 lar and synaptic levels that lead to maladaptive changes in discrete neura
 l circuits that drive behavioral symptoms. While therapeutic approaches ha
 ve typically been based on the serendipitous identification of symptom-all
 eviating compounds\, a deeper understanding of the underlying mechanisms o
 f both the pathophysiology and treatment of psychiatric disease has great 
 promise to guide the development of improved treatments. Here we focus on 
 deciphering the action of the novel antidepressant ketamine as a means of 
 identifying new G protein-coupled receptor (GPCR) antidepressant targets. 
 We first find that ketamine exerts its behavioral effects through agonism 
 of mu-opioid receptors which are enriched on the axons of SST+ interneuron
 s in the medial prefrontal cortex. mPFC SST+ interneurons both drive the r
 apid initiation of ketamine’s circuit and behavioral effects and serve a
 s key mediators of the effects of chronic unpredictable stress via axonal 
 hypertrophy which leads to excessive mPFC inhibition. Driven by these mech
 anistic findings\, we use cell type-targeted RNA sequencing to identify SS
 T+-enriched GPCRs which can drive antidepressant responses upon agonism or
  antagonism. Most notably\, synergistic targeting of multiple SST+ enriche
 d GPCRs enables antidepressant responses with enhanced efficacy and reduce
 d side effect profiles compared to ketamine. Together this study reveals n
 ew mechanistic insights with promise to improve antidepressant strategies 
 and reveals a general approach to identifying new therapeutic GPCR targets
  for brain disorders. 
LOCATION:Bryan Matthew’s Seminar Room\, Physiology Building\, Downing Si
 te
END:VEVENT
END:VCALENDAR