Center for Neuroscience and Cell Biology · University of Coimbra
How do signaling scaffolds coordinate information processing across brain and body?
Central vision
Maintaining a precise balance between excitation and inhibition (E/I) is essential for neuronal homeostasis and healthy brain function.
Although glutamatergic (excitatory) neurons make up nearly 80% of brain neurons, the smaller population of GABAergic (inhibitory) neurons exerts a disproportionately large influence on network excitability, synchronization, and information processing.
Over the past two decades, our research has shown that synapses are biochemically and functionally integrated with processes in the nucleus, soma, and dendrites. This integration reveals direct molecular links between synaptic signaling and the mechanisms underlying brain pathology.
Three mechanistic axes
Extracellular matrix axis · Project 1
The ECM regulates perineuronal net integrity to gate cortical plasticity across the lifespan. In the bone marrow niche it coordinates homeostasis, linking cancer and aging.
Key work: Cramer et al., Mol Psychiatry 2026 · Cramer et al., Cell Reports 2023
Nuclear axis · Project 2
Activity-driven nuclear condensates couple synaptic signaling to RNA-processing programs that govern sleep homeostasis and circuit-state transitions.
Key work: Noya et al., Science 2019 · Mircsof et al., Nat Neurosci 2015
Synaptic / systemic axis · Project 3
Synaptic scaffolding proteins extend their regulatory reach into nuclear transcription, brown-fat metabolism, redox balance, and sex-specific circadian physiology.
Gephyrin links to conditions ranging from bipolar disorder, autism, stroke and epilepsy to sleep disorders, perimenopause and metabolic disease.
Key work: Campbell et al., Mol Psychiatry 2024 · Tyagarajan & Fritschy, Nat Rev Neurosci 2014
Inside the GABAergic synapse
Gephyrin assembles beneath GABAA receptors into a lattice that kinases, phosphatases and SUMOylation remodel. Its state sets how strongly a neuron is inhibited and carries signals beyond the synapse.
Protein heterogeneity at GABAergic postsynapses. GABAAR subunits assemble differentially into heteropentameric receptors. Gephyrin, the main scaffolding protein at inhibitory postsynaptic sites, interacts with diverse cytosolic and membrane proteins to form a signaling network. Collybistin, which exists as several splice isoforms, is the only RhoGEF known to drive inhibitory synapse assembly through gephyrin. Gephyrin-independent GABAergic synapses also exist (left), and how they are assembled and maintained is still unclear. Several protein complexes that support trans-synaptic signaling have been uncovered in recent years.
Publications
Cramer TML, Hannan SB, Pretre L, Bear MF, Hensch TK, Tyagarajan SK
Molecular Psychiatry · Published 11 June 2026
Campbell BFN, Cruz-Ochoa N, Otomo K, Lukacsovich D, Espinosa P, Abegg A, Luo W, Bellone C, Földy C, Tyagarajan SK
Molecular Psychiatry 29:2510–2526 · Open access
Cramer T et al., Tyagarajan SK
Science Advances
Noya SB et al., Tyagarajan SK, Brown SA
Science
Tyagarajan SK, Fritschy J-M
Nature Reviews Neuroscience
Over 50 publications on inhibitory synapses, gephyrin, the extracellular matrix and sleep.
People
Principal Investigator · Biochemistry of Brain Diseases
Shiva studies how synaptic proteins act at and beyond the synapse to shape brain circuits, behavior and vulnerability to disease. Before joining CNC-UC, he worked at the Institute of Pharmacology and Toxicology, University of Zurich, where much of the lab's research on the inhibitory scaffold protein gephyrin began.
ORCID 0000-0003-0074-1805 CNC profile DCV profile Ciência Vitae LinkedIn
Open positions
We welcome curious, rigorous people who want to connect molecules to circuits, behavior and disease.
Master's
A 9 to 12 month research project inside an ongoing study, or a new project with regular mentoring.
Doctoral
An independent project on one of the three mechanistic axes, from biochemistry to in vivo function.
Postdoctoral
Lead a research line and help shape the lab's direction, with support for fellowship applications.
How to apply. Send a CV, a short statement of your research interests, and contact details for two referees. Please name the position in the subject line.
shiva.tyagarajan@cnc.uc.pt
Beyond the bench
Lab spin-off venture
Founded by Shiva Tyagarajan to develop a new generation of precision CNS therapy. Through more than 18 years of research, the lab identified a novel way to modulate synapses through a scaffolding protein.
The approach makes CNS treatment more targeted and widens the therapeutic window for drugs with novel, highly potent and non-addictive profiles. With a proprietary drug-screening platform, the team is now advancing hits into lead compounds.
Science outreach · 2015–2020
Shiva and his wife co-founded the non-profits Science Xplore (Portugal) and Science Xplore Suisse (Switzerland), where he served as Vice-President. From 2015 to 2020 they brought scientists and artists together to share science with young people aged 12 to 18.
Working with researchers from the University of Coimbra and the University of Aveiro, and with Ciência Viva Portugal, they ran week-long ART LAB workshops during school breaks. The program ended in 2020 when the COVID-19 pandemic began.
Contact
shiva.tyagarajan@cnc.uc.pt