Brainmap: Down with mGluR5, up with synaptic density: Insights from PET imaging studies


Event Details


Irina Esterlis, PhD
Assistant Professor of Psychiatry, Yale University

Abstract:

Metabotropic glutamatergic receptors have received a lot of attention in the past decade due to their ability to mediate mood and cognitive processes in animal models, and due to the emerging role of glutamate dysfunction in psychiatric disorders. We designed several experiments to determine the role of mGluR5 in mood and trauma disorders. Our data show that although mGluR5 ligands do not compete directly with the glutamate site on mGluR5, there is an inverse association between mGluR5 availability and glutamate. Further, contrary to the previously published study in younger adults, our large study in MDD suggests that mGluR5 is not involved in mood symptoms of depression, but that rapid downregulation of mGluR5 is associated with a reduction in anxiety symptoms. Additional data suggest upregulation of mGluR5 in individuals with PTSD, with individuals with more symptomatology having higher receptor levels. In parallel, we conducted postmortem work in PTSD, examining mGluR5 and glucocorticoid markers that suggest upregulation of mGluR5 due to a combination of upregulated SHANK-1 and downregulation of GC proteins in PTSD. Obtaining these markers in parallel with PET imaging work will greatly elucidate our understanding of mGluR5 involvement in PTSD. The second portion of the talk will focus on our novel examinations of synaptic density imaging in vivo by imaging synaptic vesicle glycoprotein (SV2A) -an excellent marker of synaptic density in the brain. Initial rodent and human work show reductions in synaptic density due to stress/depression, with the extent of the reduction being associated with affective and cognitive dysregulation in individuals with MDD. Studies are ongoing to examine the extent of this reduction in MDD and PTSD, and its association to symptomatology.

About the Speaker:

Irina received her PhD in clinical neuropsychology from UConn in 2005 and came to Yale for postdoctoral fellowship in molecular neuroimaging of addiction disorders. From then on, she was hooked on SPECT and PET work, and with the receipt of K01 award in 2011 she has focused on elucidating the molecular changes associated with mood and comorbid disorder. The earlier stage of her career was dedicated to the acetylcholinergic system and she developed a novel paradigm to interrogate the cholinergic system in vivo in a human. For this, she won recognition from SNMMI and ACNP societies. Presently, their group is using this paradigm to investigate changes in acetylcholinergic system associated with smoking and cessation. Receipt of NARSAD and DANA awards allowed her to start a series of projects with mGluR5. In collaboration with Christine DeLorenzo, she has examination the effects of glutamate surge on mGluR5 in vivo as well as provided elucidation for the interesting same-day test retest studies at the mGluR5 site. She also received R01 from NIMH to examine mGluR5 as a biomarker of bipolar depression (versus unipolar) and whether it underlies the positive emotion dysregulation observed in bipolar disorder. With the addition of the PTSD work in collaboration with the VA, she likely has the largest mGluR5 data set. Most recently, Irina took advantage of the UCB-J development – a radioligand believed to provide indirect quantification of synaptic density – and has extended her work to look at synaptic density changes associated with mood and trauma disorders, both in animal models of stress as well as in vivo in humans.