New chemical trail leads to the secrets of memory and depression

Almost each one of us lives in the belief that he/she directs his/her mind completely consciously and fully independently. In fact, many human behaviors, such as addiction or tendency for depression, are determined by complex physico-chemical processes occurring in different brain structures. Particularly important here are the mechanisms that work in synapses, that is in areas where neurons transmit signals. The scientists from the Nencki Institute of Experimental Biology of the Polish Academy of Sciences in Warsaw, in collaboration with the University College of London, the German Center for Neurodegenerative Diseases and the Hannover Medical School, have just unveiled another secret of the chemical enigma hidden here. For the first time they described a whole new signal path associated with 5-HT7R, one of the receptors present in dendritic spines within synapses. The results are presented in the well-known biological journal Cell Reports. The editorial office further emphasized the importance of the publication, placing the associated graphics on the cover.

"Synapses are particularly important in communication between neurons, and so in areas where these cells come into contact with their neighbors. Understanding of processes taking place here is still a major challenge of great importance for science and medicine," says Prof. Jakub Wlodarczyk, head of the Laboratory of Cell Biophysics at the Nencki Institute. "Our contribution was to describe the previously unknown signaling pathways, associated with one of the serotonin receptor variants. Knowing this path, we can begin to think, for example, of new ways of chemical control of certain cases of depression."

Man is his/her memory. Deprived of the possibility of preserving own observations and experiences, we would not be able to associate events, form the personality characteristic only for us, or function socially. We owe remembering and associating to the extraordinary ability of the brain to plastic modeling of the structure of connections between neurons. Key role here is played by processes occurring in synapses, i.e. areas where numerous and branched neuronal processes (dendrites and axons) come into contact with other cells (mostly adjacent neurons). Communication disorders between the neurons are at the root of Parkinson's or Alzheimer's disease, and lead to addiction, depression, schizophrenia, autism or epilepsy.

Scientists from the Nencki Institute of Experimental Biology focused their attention on biological processes that occur between the extracellular matrix (the substance that surrounds neurons, containing many different proteins), and dendritic spines, small processes largely covering the dendrites. Contemporary research indicates that both learning and memorization are related to the number, size and shape of dendritic spines.

"The larger the spine, the more different types of receptors that capture some of the chemical compounds from the environment can be found there. These compounds are secreted by the adjacent neuron to the extracellular matrix in the synaptic cleft and participate in the signal transmission. Our group was interested in the processes occurring with the participation of one of the types of serotonin receptors, i.e. the 5-HT7R receptor. Many antipsychotic or antidepressant substances interact directly with this receptor. Furthermore, it has recently been discovered that the pharmacological blocking of this receptor has antidepressant effects," explains PhD Monika Bijata (Nencki Institute), for whom the issues discussed were the basis for her doctoral dissertation.

The research conducted, on the Polish side funded by the HARMONIA grant of the National Science Centre and by the TANGO grant of the National Center for Research and Development, allowed to determine that when the neurotransmitter activates the 5-HT7R receptor, the extracellular matrix is re-modeled. For the first time it was demonstrated that the 5-HT7R receptor forms CD44 protein complexes and that the CD44 can be cleaved by the enzyme secreted by the stimulated receptor: the MMP9 metalloprotease. As a result of cutting, another protein, i.e. Cdc42, is activated. It is the one which, through the effect on the actin cytoskeleton, contributes to the growth of dendritic spine. It has also been proven that the spines enlarged as a result of the operation of the described signaling pathways, are indeed functional.

"Now, when we already know the signaling pathways associated with the 5-HT7R receptor activity, it will be easier for us to select molecular targets for new, potentially more effective antidepressant therapies. We can try to block the MMP9 enzyme activity, reduce the CD44 protein cleavage or specifically affect another part of the path," says PhD. Bijata.

"We gained the knowledge about the chemical changes in the extracellular matrix that occur during the activation of the 5-HT7R receptor, while exploring the neurons. However, it can also be used in relation to some other types of cells, such as cancer cells. This is the way to another therapies, for example, preventing cancers," complements prof. Wlodarczyk.

The experimental part relating to the experiments conducted on animals deprived of the 5-HT7R receptor was performed by PhD Bijata during her scientific internship at the Prof. Evgeni Ponimaskin laboratory from the Hannover Medical School.

The Nencki Institute of Experimental Biology of the Polish Academy of Sciences has been established in 1918 and is the largest non-university centre for biological research in Poland. Priority fields for the Institute include neurobiology, neurophysiology, cellular biology and biochemistry and molecular biology -- at the level of complexity from tissue organisms through cellular organelles to proteins and genes. There are 31 labs at the Institute, among them modern Laboratory of Confocal Microscopy, Laboratory of Cytometry, Laboratory of Electron Microscopy, Behavioural and Electrophysiological Tests. The Institute is equipped with state-of-the-art research equipment and modernized animal house, where lab animals are bred, also transgenic animals, in accordance with the highest standards. Quality of experiments, publications and close ties with the international science community, place the Institute among the leading biological research centres in Europe.