Lisa Janina Klotz-Weigand

Research Interest

In the auditory pathway, sound encoding is ensured via synaptic transmission by specialized chemical synapses, so called ribbon synapses at inner hair cells (IHC) that contact post-synaptic spiral ganglion neurons. Toxic environmental stimuli such as noise trauma can lead to excessive glutamate concentrations in the synaptic cleft. This, is in turn might result in degeneration and loss of these sensory synapses that ultimately leads to varying forms of hearing impairment. However, G protein-coupled receptors such as metabotropic glutamate receptors (mGluR) can couple to inhibitory signal pathways that limit pre-synaptic glutamate release and thereby protect the synapse from toxic stimuli. The family of mGluRs consists of eight subtypes (mGluR1 to mGluR8) that are subdivided into three groups. Especially members of group II and III have been associated with protective functions. Furthermore, several mGluR members can be alternatively spliced at the intracellular C-terminus to generate isoforms. In general, mGluRs can assemble into homo- or heterodimers. It has been described that heterodimeric mGluRs have distinct characteristics in their kinetics, glutamate affinity, receptor targeting and coupling efficacy to signal pathways compared to their homodimeric counterparts. In preliminary work, we described several members of group II and III at the IHC ribbon synapses, including mGluR7 isoforms (a and b). Interestingly, mGluR7 is the only mGluR type that has been correlated with age-related and noise‐induced hearing deficits for over ten years. We are currently investigating the composition of mGluR7 and other pre-synaptic mGluRs using a set of complementary anatomical, biochemical and pharmacological tools at IHC ribbon synapses. In addition, we plan to study their function by a combination of electrophysiological and physiological techniques.

Figure 1: Metabotropic glutamate receptors as central elements of inhibitory feedback loops at the inner hair cell ribbon synapse.

Top: Inner hair cells form ribbon synapses that store the excitatory neurotransmitter glutamate (dark grey circles) in synaptic vesicles that are tethered to a central pre-synaptic ribbon (light grey oval). Upon activation, release of glutamate (blue arrows) activates mGluR2 (light blue oval) on post-synaptic spiral ganglion neurons. At the same time, pre-synaptic mGluR4, mGluR7a, mGluR7b and mGluR8b are activated, possibly inhibiting further glutamate release into the synaptic cleft (red lines). Both, pre- and post-synaptic mGluRs could prevent excitotoxic effects at this synapse.

Bottom: The left panel shows a confocal z-projection of a mouse cochlear wholemount co-labelled for mGluR7a (green) and the pre- and post-synaptic markers Ribeye (red) and PSD95 (magenta), respectively. DAPI (cyan) visualizes the localization of cellular nuclei. The boxed area is enlarged in the two middle panels that show mGluR7a perfectly superimposed with Ribeye, while PSD95 is more distant. The right panel shows an Imaris 3D reconstruction of one individual ribbon synapse. The letters a, b and c refer to different distances between the centres of gravity (white balls) of the labellings.

Biography

2020 – present	Postdoctoral Follow, Institute of Biochemistry, FAU Erlangen
2019	Dr.rer. nat (PhD ), Institute of Biochemistry, FAU Erlangen
2015	Master of Science in Biochemistry and Molecular Biology, University of Bayreuth

Awarded Grants and Fellowships

2023 –	Metabotropic glutamate receptor type 7 dimers at inner hair cell ribbon synapses of the mammalian cochlea: protection against hearing loss“ Sachbeihilfe der Deutschen Forschungsgemeinschaft (DFG)
2021 – 2023	Protective function of mGluR7 in the cochlea (ELAN Grant by the interdisciplinary centre for clinical research of the Universitätsklinikum Erlangen)

Selected Publications

L. Klotz-Weigand and R. Enz, “Metabotropic Glutamate Receptors at Ribbon Synapses in the Retina and Cochlea,” Cells, vol. 11, no. 7. MDPI, 01-Apr-2022.

L. Klotz and R. Enz, “MGluR7 is a presynaptic metabotropic glutamate receptor at ribbon synapses of inner hair cells,” FASEB J., vol. 35, no. 11, pp. 1–15, 2021.

W. Bachert, L. Klotz, H. Sticht, and R. Enz, “Homodimerization of a proximal region within the C-terminus of the orphan G-protein coupled receptor GPR179,” Neurochem. Int., vol. 149, Oct. 2021.

L. Klotz, O. Wendler, R. Frischknecht, R. Shigemoto, H. Schulze, and R. Enz, “Localization of group II and III metabotropic glutamate receptors at pre- and postsynaptic sites of inner hair cell ribbon synapses,” FASEB J., vol. 33, no. 12, pp. 13734–13746, Dec. 2019.

F. Mascia, L. Klotz, J. Lerch, M. H. Ahmed, Y. Zhang, and R. Enz, “CRIP1a inhibits endocytosis of G-protein coupled receptors activated by endocannabinoids and glutamate by a common molecular mechanism,” J. Neurochem., vol. 141, no. 4, pp. 577–591, 2017