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Where to Look for New Treatments for Alcoholism?
Of mice and men – from small protein to big motivation

Head: Leszek Kaczmarek, Ph.D.

The team: Dr. Anna Beroun, Dr. Katarzyna Biegańska, Ewa Banach, Marta Doliwa, Katarzyna Gralec, Dr. Mayank Chaturvedi, Dr. Artur Czupryn, Dr. Adam Gorlewicz, Dr. Tomasz Jaworski, Dr. Katarzyna Kalita-Bykowska, Dominik Kanigowski, Danylo Khomiak, Klaudia Kogut, Anna Krysiak, Agnieszka Kostrzewska-Księżyk, Tomasz Lebitko, Diana Legutko, Katarzyna Łepeta, Paweł Matryba, Lena Majchrowicz, Dr. Jarosław Mazuryk, Dr. Piotr Michaluk, Dr. Shiladitya Mitra, Karolina Nader, Dr. Jewgeni Nikolajew, Dr. Monika Pawłowska, Dr. Alicja Puścian, Dr. Barbara Pijet, Dr. Rafał Płatek, Dr Emilia Rejmak-Kozicka, Piotr Rogujski, Dr Izabela Rutkowska-Włodarczyk, Olga Markina, Ahmad Salamian, Bogusia Sudoł-Rutkowska, Dr. Marzena Stefaniuk, Dr. Joanna Urban-Ciećko, Behnam Vafadari, Zbigniew Zieliński

Our research aim is to understand brain-mind connection. We believe that is is possible to localize specific mind functions into the brain and then reveal their molecular and cellular underpinnings. The window to understand mind is learning and memory that can be successfully studied in experimental animals. At the molecular and cellular levels , synaptic plasticity appears to provide plausible explanation for those phenomena. Twenty five years ago, together with H.J. Matthies and his colleagues from Magdeburg and simultaneously with K.V. Anokhin and his coworkers in Moscow, we have discovered gene expression in the mammalian brain in learning. The first such gene was c-fos, encoding a component of transcription factor AP-1. This led us to identify c-Fos/AP-1 such target genes in activated neurons as TIMP-1 (tissue inhibitor of matrix metalloproteinases) and MMP-9 (matrix metalloproteinase). Over the last dozen years we have shown that MMP-9 is produced and released at the excitatory synapses in response to enhanced neuronal activity to play a paramount role in the synaptic plasticity, learning and memory as well as in neuropsychiatric disorders, including epilepsy, alcohol addiction, schizophrenia and bipolar disorder. Presently, our major research effort is focused on MMP-9 and its fundamental role in controlling morphological and functional plasticity of the excitatory synapses, especially in the central nucleus of the amygdala, which we have implicated as pivotal for the appetitive learning.

Selected Publications

Lepeta K., Purzycka K., Pachulska-Wieczorek K., Mitjans M., Begemann M., Vafadari B., Bijata K., Adamiak R., Ehrenreich H., Dziembowska M., Kaczmarek L., A normal genetic variation modulates synaptic MMP-9 protein levels and the severity of schizophrenia symptoms. EMBO Molecular Medicine, in press.
de Hoz L., Gierej D., Lioudyno L., Jaworski J., Blazejczyk M., Cruces-Solís H., Beroun A., Lebitko T., Nikolaev T., Knapska E., Nelken I., Kaczmarek L. Blocking c-Fos expression reveals the role of auditory cortex plasticity in sound frequency discrimination learning. Cerebral Cortex, in press.
Stefaniuk M., Beroun A., Lebitko T., Markina O., Leski S., Meyza K., Grzywacz A., Samochowiec J., Samochowiec A., Radwanska K., Kaczmarek L. Matrix metalloproteinase-9 and synaptic plasticity in the central amygdala in control of alcohol seeking behavior. Biological Psychiatry, 81: 905–906, 2017.
van der Kooij M. , Fantin M. , Rejmak E., Grosse J., Zanoletti O., Fournier C., Ganguly K., Kalita K., Kaczmarek L., Sandi C. Role for MMP-9 in stress-induced down-regulation of nectin-3 in hippocampal CA1 and associated behavioral alterations. Nature Communications , 5: 4995, 2014.
Stawarski M., Rutkowska-Wlodarczyk I., Zeug A., Bijata M., Madej H., Kaczmarek L., Wlodarczyk J. Genetically encoded biosensor for imaging MMP-9 activity. Biomaterials, 35: 1402-1410, 2014.
Janusz A., Milek J., Perycz M., Pacini L., Bagni C., Kaczmarek L., Dziembowska M. The Fragile X Mental Retardation Protein regulates Matrix Metalloproteinase 9 mRNA at synapses. Journal of Neuroscience, 33: 18234–1824, 2013.
Knapska E., Lioudyno V., Kiryk A., Gorkiewicz T., Mikosz M., Michaluk P., Gawlak M., Chaturvedi M., Mochol G., Balcerzyk M., Wojcik D.K., Wilczynski G.M., Kaczmarek L. Reward learning requires activity of matrix metalloproteinase-9 in the central amygdala. Journal of Neuroscience, 33: 14591–14600, 2013.
Dziembowska M., Milek J., Janusz A., Rejmak E., Romanowska E., Gorkiewicz T., Tiron A., Bramham C., Kaczmarek L. Activity-dependent local translation of matrix metalloproteinase-9. Journal of Neuroscience, 32: 14538 –14547, 2012.
Knapska E., Macias M., Mikosz M., Nowak A., Owczarek D., Wawrzyniak M., Pieprzyk M., Cymerman I.A., Werka T., Sheng M., Maren S., Jaworski J., Kaczmarek L., Functional anatomy of neural circuits regulating fear and extinction. Proceedings of the National Academy of Sciences USA, 42: 17093-17098, 2012.

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