P9: cGMP signaling and its role in autistic and cognitive auditory processing disabilities
Aims
To understand the interaction of stress pathways and cGMP signaling during central auditory processing deficits that are linked to autism spectrum disorders as well as age and noise induced hearing loss.
Questions and Methods
cGMP and the Brain
- Analyze whether changes in NO-GC/GC-A expression begin before or after hearing onset in an autism-like mouse model (BDNFPax2KO) that ha immature fast auditory processing. Further test whether pharmacological manipulation can influence the phenotype.
- Analyze if BK channels shown to be controlled by cGMP and hypothesized to be involved in autism spectrum disorder are dysfunctional in BDNFPax2KO.
- Analyze the MR/GR-induced influence on NO-GC-/GC-A expression before and after hearing onset in MR and/or GR conditional knock-out mice.
- Analyze the role of GC-A for stress-controlled memory-linked hemodynamic response changes during neural gain in TMX-induced GC-AcKO mice.
- Aiming to improve insight into the mechanism of how GC-A/cGMP may affect hemodynamic responses during LTP and neurovascular coupling (NVC) a GC-AcKO mouse line crossed with a reporter mouse line (Blev mouse) enabling the visualization of capillaries will be studied.
Boston Internship
Jacob Lab
In the Jacob lab in Boston, the doctoral researchers will trained in
- analyzing for spine maturation differences and spine density using multiphoton microscopy on hippocampal slices in animal models for autism spectrum disorder in analogy to (Alexander et al. 2020, Wickham et al. 2021).
- EEG and LTP technology as well as double mRNA and protein detection as e.g. NO-GC / GC-A mRNA and excitatory / inhibitory marker proteins from Tübingen to Boston. These technologies will also be useful resources for many projects of the planned RTG, especially projects H Schmidt (P7), R Lukowski (P2).
Boston Co-mentor
Prof. Michele Jacob, PhD
Link to Boston researcher lab
Doctoral Students
Philine Marchetta (graduated in July 2022)
Philine Marchetta studied biology at the University of Tübingen and earned her Bachelor’s degree in 2016 in the department of Animal Physiology. She went to Marburg to study Molecular and Cellular Neuroscience for her master’s and earned her degree in 2018. Her thesis was in the field of molecular neurophysiology with cooperation to the University Hospital of Tübingen. During her doctoral studies in the laboratory of Marlies Knipper in the department of Molecular Physiology of Hearing she will focus on the influence of cGMP pathways in the brain, especially the auditory processing but also cognition, plasticity and disorders such as autism spectrum. She is interested in electrophysiological methods as well as imaging and behavioral tests.
Philine is the first doctoral fellow who graduated from the GRK 2381. She is currently a postdoctoral research fellow in the field of sensory neuroscience in the University of California, San Francisco, USA.
Dila Calis
Dila studied Bioengineering and Genetics at Istanbul Bilgi University in Turkey for her Bachelor’s degree and she completed her Master’s degree in Cognitive and Clinical Neuroscience with Specialization of Drug Development & Neurohealth in Maastricht University from Netherlands. During her bachelor thesis she investigated the neuronal basis of behavioral despair at Bogazici University. For her master thesis she worked on the vulnerability to stress disorders at Douglas Mental Health University Institute in Canada. She started her PhD in Marlies Knipper’s group which is “Molecular Physiology of Hearing” at the Hearing Research Center in Tübingen where she will study cGMP signaling in hearing impairments and models for autism spectrum disorders.
Morgan Hess (associated PhD student)
Morgan Hess obtained her B.A. in Experimental Psychology from the University of South Carolina. She then obtained her M.Sc. in Neural and Behavioral Sciences from the University of Tübingen, where she pursued research on the auditory system. During her first lab rotation with Prof. Dr. Marlies Knipper, her project focused on stress, cGMP, and hearing. In her second lab rotation, she worked on genetic epidemiology of hereditary hearing loss under the supervision of Dr. Barbara Vona. She completed her master thesis in the lab of Prof. Dr. Marlies Knipper, where she investigated sound enrichment on a mouse model with autism-like characteristics. For her ongoing doctoral studies in the lab of Prof. Dr. Marlies Knipper, she will examine the role of cGMP at the crossroads of hearing, stress, and autism.
Key Publications
Calis D, Hess M, Marchetta P, Singer W, Modro J, Nelissen E, Prickaerts J, Sandner P, Lukowski R, Ruth P, Knipper M, Rüttiger L. Acute deletion of the central MR/GR steroid receptor correlates with changes in LTP, auditory neural gain, and GC-A cGMP signaling. Front Mol Neurosci 2023, 16:1017761.
Eckert P, Marchetta P, Manthey MK, Walter MH, Jovanovic S, Savitska D, Singer W, Jacob MH, Ruttiger L, Schimmang T, Milenkovic I, Pilz PKD, Knipper M. 2021. Deletion of BDNF in Pax2 lineage-derived interneuron precursors in the hindbrain hampers the proportion of excitation/inhibition, learning, and behavior. Front Mol Neurosci 14:642679. doi:10.3389/fnmol.2021.642679
Marchetta P, Eckert P, Lukowski R, Ruth P, Singer W, Rüttiger L, Knipper M. Loss of central mineralocorticoid or glucocorticoid receptors impacts auditory nerve processing in the cochlea. iScience 2022, 26;25(3):103981.
Marchetta P, Mohrle D, Eckert P, Reimann K, Wolter S, Tolone A, Lang I, Wolters M, Feil R, Engel J, Paquet-Durand F, Kuhn M, Knipper M, Ruttiger L. 2020a. Guanylyl cyclase A/cGMP signaling slows hidden, age- and acoustic trauma-induced hearing loss. Front Aging Neurosci 12:83. doi:10.3389/fnagi.2020.00083
Savitska D, Hess M, Calis D, Marchetta P, Harasztosi C, Fink S, Eckert P, Ruth P, Rüttiger L, Knipper M, Singer W. Stress affects central compensation of neural responses to cochlear synaptopathy in a cGMP-dependent way. Front Neurosci 2022, 16:864706.