Okur, Zeynep. Bone Morphogenetic Proteins as regulators of cortical excitation and inhibition. 2024, Doctoral Thesis, University of Basel, Faculty of Science.
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Abstract
Plasticity is the underlying mechanism for neuronal circuits to develop and adapt to the environment for organisms to regulate different body states, learn new tasks, form memories and use their cognitive abilities. Over the last century, studies demonstrated that neurons utilize the plethora and variety of their synaptic properties to store and integrate the environmental cues on shorter timescales from milliseconds to hours. However, how neurons, in particular synapses, adapt to longer periods of stimuli which is essential for learning a new task and memory consolidation, remains largely unknown.
Secreted molecules, especially growth factors, are great candidates for such adaptations in the brain areas such as cortex where multiple types of cells constantly work in harmony and exchange information to adapt to sensory stimuli. In this thesis, I investigated whether Bone Morphogenetic Proteins (BMPs), key players of the patterning during embryonic development, are re-utilized as a transcellular signal underlying homeostatic plasticity in the adult somatosensory cortex.
BMPs are ligands of the transforming growth factor family (TGF) which are encoded by more than 20 genes in vertebrates. I first contributed to a collaborative study with the group of Ralf Schneggenburger in EPFL, Lausanne. In this project, we explored if BMP signaling regulates the development of inhibitory long-term potentiation (iLTP) from Parvalbumin interneurons (PV interneurons) onto layer 4 principal cells in the primary auditory cortex (A1) during critical period plasticity. Conditional/genetic deletion of BMP receptor-1a (Bmpr1a) and 1b (Bmpr1b) demonstrated that loss of BMP signaling in PV interneurons results in disruption of iLTP formation onto layer 4 principal neurons.
In my main project, I screened BMP ligands to identify their sites of expression in the mouse neocortex and examined whether neuronal network activity can mobilize the signaling. For the first time, I demonstrated that the BMP pathway is active in mature neurons of the mouse brain and can be recruited by neuronal activity. By advancing a reporter generated from BMP responsive element of the target genes, I showed that BMP2 mobilization from principal cells are responded by Parvalbumin interneurons through SMAD1, a critical transcriptional mediator of the BMP pathway. This was quite striking as this is the first evidence that BMP signaling can be transcellularly signaled between the key players of excitation-inhibition balance in the sensory cortices. Next, I coupled Chromatin immunoprecipitation (ChiP) with RNA sequencing and identified target genes of BMP2 ligand in cortical neurons. Surprisingly, we found that the SMAD1 transcription factor regulates expression of select activity-induced immediate early genes (IEGs), genes encoding for extracellular matrix components, and glutamatergic synaptic proteins. Therefore, I focused my further experiments on the investigation of synaptic drive onto Parvalbumin interneurons to ask if loss of SMAD1 from Parvalbumin interneurons cause alterations in their synaptic connectivity and cellular properties. By coupling electrophysiological, anatomical and behavioral analyses, I demonstrated that BMP2-SMAD1 signaling is essential to maintain excitation-inhibition in balance in the adult somatosensory cortex.
In summary, this work reveals that developmental signaling molecules are re-used for trans-cellular signaling in neurons to establish synaptic connectivity during the critical periods and maintain excitation-inhibition in balance in the adult cortex.
Secreted molecules, especially growth factors, are great candidates for such adaptations in the brain areas such as cortex where multiple types of cells constantly work in harmony and exchange information to adapt to sensory stimuli. In this thesis, I investigated whether Bone Morphogenetic Proteins (BMPs), key players of the patterning during embryonic development, are re-utilized as a transcellular signal underlying homeostatic plasticity in the adult somatosensory cortex.
BMPs are ligands of the transforming growth factor family (TGF) which are encoded by more than 20 genes in vertebrates. I first contributed to a collaborative study with the group of Ralf Schneggenburger in EPFL, Lausanne. In this project, we explored if BMP signaling regulates the development of inhibitory long-term potentiation (iLTP) from Parvalbumin interneurons (PV interneurons) onto layer 4 principal cells in the primary auditory cortex (A1) during critical period plasticity. Conditional/genetic deletion of BMP receptor-1a (Bmpr1a) and 1b (Bmpr1b) demonstrated that loss of BMP signaling in PV interneurons results in disruption of iLTP formation onto layer 4 principal neurons.
In my main project, I screened BMP ligands to identify their sites of expression in the mouse neocortex and examined whether neuronal network activity can mobilize the signaling. For the first time, I demonstrated that the BMP pathway is active in mature neurons of the mouse brain and can be recruited by neuronal activity. By advancing a reporter generated from BMP responsive element of the target genes, I showed that BMP2 mobilization from principal cells are responded by Parvalbumin interneurons through SMAD1, a critical transcriptional mediator of the BMP pathway. This was quite striking as this is the first evidence that BMP signaling can be transcellularly signaled between the key players of excitation-inhibition balance in the sensory cortices. Next, I coupled Chromatin immunoprecipitation (ChiP) with RNA sequencing and identified target genes of BMP2 ligand in cortical neurons. Surprisingly, we found that the SMAD1 transcription factor regulates expression of select activity-induced immediate early genes (IEGs), genes encoding for extracellular matrix components, and glutamatergic synaptic proteins. Therefore, I focused my further experiments on the investigation of synaptic drive onto Parvalbumin interneurons to ask if loss of SMAD1 from Parvalbumin interneurons cause alterations in their synaptic connectivity and cellular properties. By coupling electrophysiological, anatomical and behavioral analyses, I demonstrated that BMP2-SMAD1 signaling is essential to maintain excitation-inhibition in balance in the adult somatosensory cortex.
In summary, this work reveals that developmental signaling molecules are re-used for trans-cellular signaling in neurons to establish synaptic connectivity during the critical periods and maintain excitation-inhibition in balance in the adult cortex.
Advisors: | Scheiffele, Peter |
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Committee Members: | Affolter, Markus and Greenberg, Michael Eldon |
Faculties and Departments: | 05 Faculty of Science > Departement Biozentrum > Neurobiology > Cell Biology (Scheiffele) |
UniBasel Contributors: | Okur, Zeynep and Scheiffele, Peter and Affolter, Markus |
Item Type: | Thesis |
Thesis Subtype: | Doctoral Thesis |
Thesis no: | 15346 |
Thesis status: | Complete |
Number of Pages: | 144 |
Language: | English |
Identification Number: |
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edoc DOI: | |
Last Modified: | 31 May 2024 04:30 |
Deposited On: | 30 May 2024 10:08 |
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