s-palmitoylation
in stress-related disorders
SMALL CHANGES - HUGE IMPACT: THE ROLE OF S-PALMITOYLATION AND S-NITROSYLATION INTERPLAY IN THE MICE MODEL OF DEPRESSION
"Small Changes - Huge Impact: The role of S-palmitoylation and S-nitrosylation interplay in the mice model of depression” project was funded by the National Science Centre under the SONATA BIS 7 grant.
Grant number 2017/26/E/NZ4/00637
Signaling pathways were identified whose activation induces depressive behaviors in mice, and it was demonstrated that postmortem brain samples from individuals with depression reveal disruptions in these signaling pathways. Specifically, it was shown that the signaling pathway involving serotonin receptors and dependent on their palmitoylation is specifically activated during chronic stress and is crucial for the induction of depressive behaviors and changes in the structural plasticity of dendritic spines. The study investigated whether prophylactic administration of ketamine affects the structural plasticity of the brain in mice subjected to chronic unpredictable stress. Evidence was provided linking the antidepressant action of ketamine to changes in structural plasticity in the brain.
An important part of the project's implementation was the creation of a of methods and experimental approaches for analyzing post-translational modifications of proteins and methods for analyzing and statistically assessing changes in synaptic plasticity of dendritic spines. A method was developed to predict palmitoylation sites, methods for segmenting dendritic spines in 3D, and rigorous statistical methods for assessing changes in the morphology of dendritic spines.
The goal of the project was to explore the role of post-translational modifications of synaptic proteins on the structural and functional synaptic plasticity underlying stress-related disorders. Equally important was the methodological aspect of the project, which involved creating and developing methods for analyzing synaptic plasticity both at the level of the structure of dendritic spines (where the postsynaptic part of the synapse is located) and the molecular architecture of the synapse (post-translational modifications of synaptic proteins). The complexity of depressive symptoms observed in humans makes modeling depressive behaviors in rodents a challenge. As part of the project implementation, a highly reproducible protocol was proposed that allows for the creation of mouse models that mimic several aspects of depression, such as anhedonia and loss of motivation. A chronic unpredictable stress protocol was created, which induces anhedonic and stress-resistant behaviors. In this model, a differential analysis of post-translational modifications of synaptic proteins was conducted based on proteomic profiling. Using a combination of behavioral, biochemical, and imaging methods, the project analyzed signaling dependent on serotonin receptors and structural plasticity of dendritic spines in the mouse brain in a model of chronic unpredictable stress inducing depressive behaviors.
The results obtained within the SONATA BIS 7 project funded by National Science Centre grant 2017/26/E/NZ4/00637:
Ziółkowska M., Borczyk M., Cały A., Tomaszewski KF., Nowacka A., Nalberczak-Skóra M., Śliwińska MA., Łukasiewicz K., Skonieczna E., Wójtowicz T., Wlodarczyk J., Bernaś T., Salamian A., Radwanska K. Phosphorylation of PSD-95 at serine 73 in dCA1 is required for extinction of contextual fear. PLoS Biol. 2023, 21: e3002106.
Bijata M., Baczyńska E., Włodarczyk J. A chronic unpredictable stress protocol to model anhedonic and resilient behaviors in C57BL/6J mice. STAR Protoc. 2022,3:101659.
Bijata M., Bączyńska E., Müller FE., Bijata K., Masternak J., Krzystyniak A., Szewczyk B., Siwiec M., Antoniuk S., Roszkowska M., Figiel I., Magnowska M., Olszyński KH., Wardak AD., Hogendorf A., Ruszczycki B., Gorinski N., Labus J., Stępień T., Tarka S., Bojarski AJ., Tokarski K., Filipkowski RK., Ponimaskin E., Wlodarczyk J. Activation of the 5-HT7 receptor and MMP-9 signaling module in the hippocampal CA1 region is necessary for the development of depressive-like behavior. Cell Rep. 2022, 38:110532.
Krzystyniak A., Wesierska M., Petrazzo G., Gadecka A., Dudkowska M., Bielak-Zmijewska A., Kosieniak G., Figiel I., Włodarczyk J.*, Sikora E.* *co-corresponding Combination of dasatinib and quercetin improves cognitive abilities in aged male Wistar rats, alleviates inflammation and changes hippocampal synaptic plasticity and histone H3 methylation profile. Aging. 2022, 14:572.
Figiel I., Kaczyńska E., Wojtowicz T., Magnowska M., Buszka A., Bijata M., Włodarczyk J. The cell adhesion protein dystroglycan afects the structural remodeling of dendritic spines. Sci. Rep. 2022, 12:2506.
Gorinski N., Bijata M., Prasad S., Wirth A., Galil D.A., Zeug A., Bazovkina D., Kondaurova E., Kulikova E., Ilchibaeva T., Zareba-Koziol M., Papaleo F., Scheggia D., Kochlamazashvili G., Dityatev A., Smyth I., Krzystyniak A., Wlodarczyk J., Richter D.E., Strekalova T., Sigrist S., Bang C., Hobuß L., Fiedler J., Thum T., Naumenko V.S., Pandey G., Ponimaskin E. Attenuated palmitoylation of serotonin receptor 5-HT1A in brain affects receptor functions and triggers depressive symptoms. Nat. Comm. 2019, 10:3924.
Zareba-Koziol M., Bartkowiak-Kaczmarek A., Roszkowska, M. Bijata K., Figiel I, Kumar Halder A., Kamińska P., Müller F. E.,, Basu S., Zhang W., Ponimaskin E., Włodarczyk J. S-Palmitoylation of Synaptic Proteins as a Novel Mechanism Underlying Sex-Dependent Differences in Neuronal Plasticity. Int. J. Mol. Sci. 2021, 22:6253.
Gorinski N., Wojciechowski D., Guseva D., Galil D.A., Mueller F.A., Wirth A., Thiemann S., Zeug A., Schmidt S., Zareba-Kozioł M., Wlodarczyk J., Skryabin B.V. Glage S., Fischer M., Al-Samir S., Kerkenberg N., Hohoff C., Zhang W., Endeward V., Ponimaskin E. DHHC7-mediated palmitoylation of the accessory protein barttin critically regulates the functions of ClC-K chloridechannels. J. Biol. Chem. 2020, 295:5970.
Das N., Baczynska E., Bijata M., Ruszczycki B., Zeug A., Plewczynski D., Saha PK., Ponimaskin E., Wlodarczyk J.*, Basu S.* * co-corresponding 3dSpAn: An interactive software for 3D segmentation and analysis of dendritic spines. Neuroinformatics. 2021, 1-20.
Bandyopadhyay SS., Halder AK., Zaręba-Kozioł M., Bartkowiak-Kaczmarek A., Dutta A., Chatterjee P., Nasipuri M., Wójtowicz T., Wlodarczyk J.*, Basu S.* *co-corresponding. RFCM-PALM: In-Silico Prediction of S-Palmitoylation Sites in the Synaptic Proteins for Male/Female Mouse Data. Int. J. Mol. Sci. 2021, 22:9901.
Bączyńska E., Pels KK., Basu S, Włodarczyk J, Ruszczycki B. Quantification of Dendritic Spines Remodeling under Physiological Stimuli and in Pathological Conditions. Int. J. Mol. Sci. 2021, 22:4053.
Nowacka, A., Borczyk, M., Salamian, A., Wojtowicz T., Wlodarczyk J., Radwanska K., PSD-95 Serine 73 phosphorylation is not required for induction of NMDA-LTD. Sci. Rep. 2020, 10, 2054.
Schill Y., Bijata M., Kopach O., Cherkas V., Abdel-Gali D., Bohm K., Schwab MH., Matsuda M., Compan V., Basu S., Bijata K., Wlodarczyk J., Bard L., Cole N., Dityatev A., Zeug A., Rusakov DA., Ponimaskin E. Serotonin 5-HT4 receptor boosts functional maturation of dendritic spines via RhoA-dependent control of F-actin. Comm. Biol. 2020, 3:76.
Krzystyniak A., Baczynska E., Magnowska M., Antoniuk S., Roszkowska M., Zareba-Koziol M., Das N., Basu S., Pikula M., Wlodarczyk J. Prophylactic Ketamine Treatment Promotes Resilience to Chronic Stress and Accelerates Recovery: Correlation with Changes in Synaptic Plasticity in the CA3 Subregion of the Hippocampus. Int. J. Mol. Sci. 2019, 20:1726.