Doctoral defence: Maria Kaare “The involvement of NEGR1 and LSAMP in the psychiatric disorders is mediated through monoaminergic neurotransmission and changes in the systemic metabolism”

On 21 February at 15:00 Maria Kaare will defend her doctoral thesis “The involvement of NEGR1 and LSAMP in the psychiatric disorders is mediated through monoaminergic neurotransmission and changes in the systemic metabolism”.

Supervisors:
Associate Professor Mari-Anne Philips, University of Tartu

Professor Eero Vasar, University of Tartu
Research Fellow Este Leidmaa, University of Tartu

Opponent: 
Professor 
Tomi Rantamäki, University of Helsinki (Finland)

Summary
Neural cell adhesion molecules (nCAMs) are important in creating connections between neurons in the development of the nervous system, as well as in the adult brain. The current study focuses on the function on the IgLON nCAMs NEGR1 and LSAMP which have been linked with  a variety of psychiatric conditions in genome-wide association studies. Using a mouse model, we found that both LSAMP and NEGR1 were expressed in serotonergic cells. Chronic administration of SSRI escitalopram, a drug that increases serotonergic neurotransmission, caused changes in the monoamine profile in the brains of both Lsamp- and Negr1-deficient mice compared to their wild-type littermates. While higher serotonin turnover was predominant in Lsamp-deficient mice, in Negr1-deficient mice we saw changes primarily in the dopamine system. In addition, Negr1-deficient mice showed a time-dependent increase in behavioral sensitization to amphetamine, a drug which increases on dopaminergic and noradrenergic neurotransmission. This sensitization was accompanied with higher dopamine release in the striatum of Negr1-deficient mice. As NEGR1 gene is also significantly associated with body mass index in addition to psychiatric disorders in GWAS studies, we studied systemic metabolism in Negr1-deficient mice. We found that although male Negr1-deficient mice eat less of both regular and high-fat food, they gain more body weight on high-fat food, develop a stronger impairment in glucose tolerance and have more fat accumulation in the liver. Taken together, the results indicate that the effect of IgLON adhesion proteins on psychiatric disorders is mediated at least partially by the regulation of monoaminergic circuits. Our finding that NEGR1 affects systemic metabolism in addition to brain biochemistry, confirms that psychiatric syndromes should be considered as disorders of homeostasis in the whole-body.

 

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