Cellular Neurophysiology (Dr. Raul E. Guzman)

About

The “Cellular Neurophysiology” research group investigates the physiological and pathophysiological mechanisms of ClC-3 and ClC-4 and the CLCN3/4-associated neuropathologies caused by their mutant variants. The ultimate goal is to develop novel therapeutics strategies for patients with this rare disease

Research Topics

We aim to understand the role of endosomal ion transport for neuronal function, with focus on two endo-lysosomal transporters, ClC-3 and ClC-4, that regulate the pH and [Cl-] in multiple endosomal compartments. A group of neurodevelopmental disorders, in which slight changes in ClC-3 or ClC-4 transport functions cause epilepsy and intellectual disability as well as anxiety, depression, hyperactivity, and bipolar disorders, illustrate the importance of these transporters for higher brain functions. We use transgene technology (genetically modified mouse models and shRNA lentiviral transduction), patch-clamp electrophysiology, membrane cell capacitance measurements, carbon fiber amperometry, photolytic uncaging of intracellular calcium, molecular biology, and confocal microscopy to understand the cellular and molecular function of ClC-3 and ClC-4 in neuronal health and disease and to identify potential strategies for the treatment of CLCN3- and CLCN4-related disorders. Recently, our group efforts clarified the roles of such transporters for the vesicular mono-amine accumulation process and exocytosis and how Cl-/H+ exchangers regulate the electrical and excitability properties of neurons.

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Dr. Raul Guzman

IBI-1

Building 15.1 / Room 154

+49 2461/61-4035

E-Mail

Whole-cell patch-clamp analysis of WT and mutant ClC-4 currents, using transiently transfected HEK293T mammalian cells. (Modified from Front. Mol. Neurosci. https://doi.org/10.3389/fnmol.2022.872407)

A) Excitability properties recorded from wild-type neurons at the CA2 hippocampal region using acute hippocampal slice preparation. B) Richarson staining of the hippocampal region in Wild-Type, Clcn3-/- and Clcn4-/- mice.

Amperometric recordings from wild-type, Clcn3-/- chromaffin cells and rescue experiments using different ClC-3 splice variants from double ClC-3 and ClC-5 deficient cells. (Modified from Comini, M., et al., 2022, J. Neurosci. 42 (15) 3080-3095; DOI: https://doi.org/10.1523/JNEUROSCI.2439-21.2022

Members

Projekte

• Intracellular Cl-/H+ exchangers regulate the firing pattern of pyramidal neurons at the CA2 region of the Hippocampus.

• Phenotypic characterization of ClC-4 p.V523M knock-in mouse model.

• Understanding the cellular consequences of ClC-4 dysfunction in X-linked intellectual disability: a comprehensive electrophysiological and morphological characterization of hippocampal neurons from Clcn4-/- and Clcn4A549V rat models.

• Electrophysiological characterization of Clcn3^-/- and Clcn4^-/- neurons from zebrafish.

Publikationen

Sahly AN, Sierra-Marquez J, Bungert-Plümke S, Franzen A, Mougharbel L, Berrahmoune S, Dassi C, Poulin C, Srour M, Guzman RE, Myers KA. Genotype-phenotype correlation in CLCN4-related developmental and epileptic encephalopathy. Hum. Genet. (2024). https://doi.org/10.1007/s00439-024-02668-z.

He H, Li X., Guzman G.A., Bungert-Plümke S., Franzen A., Lin X., Zhu M., Peng G., Zhang W., Yu Y., Sun S., Huang Z., Zhai Q., Chen Z., Peng j., and Guzman R.E. (2024). Expanding the genetic and phenotypic relevance of CLCN4 variants in neurodevelopmental condition: 13 new patients. J. Neurol. https://doi.org/10.1007/s00415-024-12383-4

Comini, M., Sierra-Marquez, J., Guzman G.A, Franzen, A., Willuweit, A., Hidalgo, P., Fahlke, C., Guzman, R.E. (2022). CLC anion/proton exchangers regulate secretory vesicle filling and maturation in chromaffin cells. J. Neurosci. 42 (15) 3080-3095; DOI: https://doi.org/10.1523/JNEUROSCI.2439-21.2022:

Sierra-Marquez, J., Willuweit, A., Schöneck, M., Bungert-Plümke, S., Gehlen, J., Balduin, C., Müller, F., Lampert, A., Fahlke, C., Guzman, R.E. (2022). ClC-3 regulates the excitability of nociceptive neurons and suppresses inflammatory processes within the spinal sensory pathway. Front. Cell. Neurosci. DOI: 10.3389/fncel.2022.920075.

Guzman, R.E, Sierra-Marquez, J., Bungert-Plümke, Franzen, A., Fahlke, C. (2022). Functional characterization of CLCN4 variants associated with X-linked intellectual disability and epilepsy. Front. Mol. Neurosci. doi.org/10.3389/fnmol.2022.872407

He, H., Guzman, R. E., Cao, D., Sierra-Marquez, J., Yin, F., Fahlke, C., Peng, J., Stauber, T. (2021). The molecular and phenotypic spectrum of CLCN4-related epilepsy. Epilepsia 62, 1401-1415.

Grieschat, M*., Guzman, R. E*., Langschwager, K*., Fahlke, C., Alekov, A. K. (2020). Metabolic energy sensing by mammalian CLC anion/proton exchangers. EMBO Rep 21, e47872. *Equal contribution.

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Molecular and Cellular Physiology (IBI-1)

Cellular Neurophysiology (Dr. Raul E. Guzman)

About

Research Topics

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Members