Marco Pignatelli
Assistant Professor of Psychiatry WashU Medicine
Marco Pignatelli, M.D., is an Assistant Professor of Psychiatry at Washington University in St. Louis and a rising leader in synaptic physiology and neuropsychiatry. His work integrates electrophysiology, pharmacology, and behavior to uncover how experience shapes synaptic plasticity and contributes to disorders such as depression, PTSD and schizophrenia. Marco earned his M.D. and completed a Residency in Clinical Pharmacology at Sapienza University of Rome. Then, Marco moved to the United States where he continued his scientific trajectory at the National Institutes of Health. Marco has made influential discoveries on stress-induced dopamine plasticity, circuit mechanisms of emotional behavior, and synaptic deficits linked to psychiatric disease. Marco has been awarded a NARSAD Young Investigator Grant by the Brain and Behavior Research Foundation. He is currently funded by the NIH and he has recently received a Mental Health Award by the Wellcome Trust Fundation. Recently he has been selected as the recipient of the 2026 A.E. Bennett Basic Research Award by the Society of Biological Psychiatry.
Seminars
- What emerging preclinical and clinical data reveal about ketamine induced synaptic plasticity as a unifying mechanism for rapid antidepressant effects
- The role of ketamine metabolites, including HNKs, in disentangling efficacy from dissociation and informing more targeted drug design
- Progress toward non dissociative and next generation ketamine derived therapies, and how these may reshape safety, scalability, and patient access
- Lessons from S-ketamine on regulatory pathways, payer expectations, and commercial adoption; and what this means for the broader psychedelic and rapid acting psychiatry landscape
- Describe how chronic stress produces profound effort related deficits and structural atrophy in D1 medium spiny neurons of the nucleus accumbens, a hub of reward computation, and how these circuit changes map onto anhedonia in depression
- Explain how a single ketamine administration, assessed after the drug has fully cleared, induces lasting synaptic plasticity that restores activity in NAc D1 MSNs and rescues stress driven motivational impairments
- Highlight how ketamine re engages two stress sensitive excitatory pathways (medial prefrontal cortex NAc and hippocampus NAc), each contributing complementary but distinct roles in restoring reward seeking behavior
- Outline next steps to translating these circuit findings to humans using functional connectivity and morphometric data analyses as a biomarker of antidepressant treatment outcome
