Study Group of Translational Neuropsychiatry

Our current focus

At the Department of Physiology, we have studied the IgLON family of neural adhesion molecules (Negr1, Lsamp, Ntm, Opcml and IgLON5) for more than 15 years. Important model organisms have been mouse lines deficient for either Negr1, Lsamp or Ntm, and primary hippocampal cell cultures derived from these mice. We have described the twin-promoter structure that defines the anatomical expressional distribution of Lsamp, Ntm and Opcml; the mutual interactions of IgLONs have been studied in gene deficient primary cultures. In pharmacological studies we have shown how IgLONs modulate transmission in distinct neurotransmitter systems. GWAS studies from the past few years have been demonstrated that NEGR1 belongs among a few dozen of molecules that have an impact on a wide spectrum of psychiatric disorders (depression, schizophrenia, and autism).

We have shown upregulation of NEGR1 in the post mortem frontal cortex and several schizophrenia-like endophenotypes in mice deficient for Negr1. These mice display disturbances in their social behavior, enlarged lateral ventricles in the brain, and reduced hippocampal volume. The reduced number of hippocampal parvalbumin interneurons in mice deficient for Negr1 indicates that Negr1 is needed for balancing excitatory and inhibitory signals in the brain that is a prerequisite for environmental adaptation processes. Additionally, NEGR1 genetic locus is one of the ten most significant loci linked with body mass index in the human genome. Negr1 deficient mice also have disturbances in their blood glucose control and altered metabolism of lipids.

Currently our research is focused on how NEGR1 is participating in the regulation of psychiatric disorders and metabolism simultaneously. The purpose of our ongoing experiments is to clarify if the roles of NEGR1 in the brain and periphery are  independent or mediated through shared pathways. The importance of the studies lies also in the notion that psychiatric disorders are often co-morbid with systemic metabolic alterations that have to be considered in the treatment of these patients. In conclusion, the purpose of our studies is to clarify the molecular mechanisms underlying psychiatric disorders and related metabolic alterations for the better understanding, prevention and treatment of these disorders.

Grants

• Estonian Research Council: Potential biomarkers for the diagnosis, prognosis, and evaluation of treatment impact for first episode psychosis and schizophrenia spectrum disorders: translational approach (Professor Eero Vasar, GMVBS20067PR, 01.01.2020−31.12.2024)

   

Current collaborations

Estonia: 

• Tartu University Hospital, Psychiatry Clinic
• University of Tartu, Institute of Biomedicine and translational Medicine, Department of Pathological Anatomy and Forensic Medicine

International:

• Prof  Michael K.E. Schäfer, Department of Anesthesiology, Focus Program Translational Neurosciences, Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Germany

The most important publications in last five years

1. Kaare M, Mikheim K, Lilleväli K, Kilk K, Jagomäe T, Leidmaa E, Piirsalu M, Porosk R, Singh K, Reimets R, Taalberg E, Schäfer MKE, Plaas M, Vasar E, Philips M-A. High-Fat Diet Induces Pre-Diabetes and Distinct Sex-Specific Metabolic Alterations in Negr1-Deficient Mice. Biomedicines. 2021; 9(9):1148. doi.org/10.3390/biomedicines9091148 
2. Jagomäe T, Singh K, Philips MA, Jayaram M, Seppa K, Tekko T, Gilbert SF, Vasar E, Lilleväli K. Alternative Promoter Use Governs the Expression of IgLON Cell Adhesion Molecules in Histogenetic Fields of the Embryonic Mouse Brain. Int J Mol Sci. 2021 Jun 28;22(13):6955. doi: 10.3390/ijms22136955. PMID: 34203377; PMCID: PMC8268470
3. Bregin A, Kaare M, Jagomäe T, Karis K, Singh K, Laugus K, Innos J, Leidmaa E, Heinla I, Visnapuu T, Oja EM, Kõiv K, Lilleväli K, Harro J, Philips MA, Vasar E (2020). Expression and impact of Lsamp neural adhesion molecule in the serotonergic neurotransmission system. Pharmacol Biochem Behav; 198:173017.
4. Singh K, Jayaram M, Kaare M, Leidmaa E, Jagomäe T, Heinla I, Hickey MA, Kaasik A, Schäfer MK, Innos J, Lilleväli K, Philips MA, Vasar E (2019). Neural cell adhesion molecule Negr1 deficiency in mouse results in structural brain endophenotypes and behavioral deviations related to psychiatric disorders. Sci Rep. 9(1):5457
5. Singh K, Loreth D, Pöttker B, Hefti K, Innos J, Schwald K, Hengstler H, Menzel L, Sommer CJ, Radyushkin K, Kretz O, Philips MA, Haas CA, Frauenknecht K, Lilleväli K, Heimrich B, Vasar E, Schäfer MKE. Neuronal Growth and Behavioral Alterations in Mice Deficient for the Psychiatric Disease-Associated Negr1 Gene. Front Mol Neurosci. 2018 Feb 9;11:30. doi:10.3389/fnmol.2018.00030. PMID: 29479305