Research Group Simon

Our research vision is to uncover the fundamental principles that govern neuronal circuit function and selective vulnerability under both physiological and pathological conditions. We investigate how synaptic and cellular mechanisms shape behavior in health and contribute to neurodegeneration, with a focus on aminergic modulation of spinal circuits, cerebellar control of motor and cognitive behaviors, and molecular signaling pathways driving neuronal death. Motor neuron diseases such as spinal muscular atrophy (SMA) and spinal muscular atrophy with respiratory distress type 1 (SMARD1), which manifest in forms ranging from severe infantile paralysis to later-onset motor impairment, provide powerful models to dissect shared and distinct mechanisms of circuit vulnerability across motor and non-motor domains. Using advanced imaging, electrophysiology, genetic tools, and human translational studies, our long-term goal is to move beyond symptom management toward precision therapies that restore circuit integrity and improve patient outcomes.

Aminergic modulation of sensory–motor circuits in health and disease​

Our recent translational study (Simon et al., 2025, Brain) with Columbia and Johns Hopkins identified dysfunction and loss of proprioceptive synapses as conserved hallmarks of SMA. Yet, the aminergic modulation and dysfunction of proprioceptive synapses remain poorly understood. We combine super-resolution imaging, optogenetics, and whole-cell patch-clamp recordings of motor neurons and spinal presynapses to uncover synaptic mechanisms in health and their translational relevance (funded by DFG 1969/5-1, SMA Europe and RTG “Neurotune”). 

​Figure 1. Imaging of Pre-synaptic active zone proteins and neurotransmission of proprioceptive synapses. (A) Confocal image of VGluT1, a marker for proprioceptive synapse (magenta), ChAT (green), a marker for motor neurons, and Munc13-1, a marker for active zone under confocal and STED scanning conditions. Note the dramatic improvement in resolution with STED. (B) Monosynaptic EPSPs recorded in a motor neuron following proprioceptive fiber stimulation in a wild type (WT) and a SMA mouse. Paired-pulse stimulation at 10Hz reveals that neurotransmission in SMA is compromised (EPSP) response in SMA is smaller in the 2^nd response). Black triangle marks stimulus artefact.

​Cerebellar pathology as a driver of behavioral phenotypes in MN diseases​

Our recent study (Gerstner et al., 2025, Brain) revealed cerebellar dysfunction as a key driver of motor and social deficits in SMA. To dissect cerebellar contribution to cognitive alterations in SMA, we generated neuron-specific knockout mice and combine whole-patch-clamp recordings, cerebellar synaptic analyses with behavioral testing. These studies will establish causal links between cerebellar pathology and behavior in motor neuron diseases (funded by DFG 1969/7-1, Initiative SMA). 

​Figure 2. Functional assessment of cerebellar circuits. (A) Confocal image a cerebellar section in which two Purkinje cells (PCs) were intracellular recorded and filled with a fluorochrome (white) and costained with the PC marker Pcp-2. (B) Whole-cell patch-clamp recording of PC action potential firing (upper trace) following current inject (lower trace). (C) EPSCs recording in PCs following parallel fiber stimulation. Black triangles mark stimulus artefact.

Molecular signaling pathways triggering neuronal death

We have shown that p53 activation drives cell-autonomous degeneration of both MNs and Purkinje cells in SMA (Simon et al., 2017; Fletcher et al., 2017; Simon et al., 2019; Gerstner et al., 2025). To identify convergent downstream mechanisms, we will integrate transcriptomic and proteomic profiling with genetic viral validation in mouse models and extend findings to human spinal cord tissue. This study will uncover critical signaling pathways driving neuronal death and provide translational guidance for the development of therapeutic strategies (funded by DFG 1969/3-1, DFG 1969/5-1).

​Figure 3. p53 immunoreactivity in Purkinje cells and motor neurons in a mouse model of SMA. Confocal images of (A) Purkinje cells labeled with PCP2 (red) and motor neurons in (B) labelled with ChAT together with p53 (white; both in A and B)  in SMA or WT mice.

Together, these three research lines form a coherent program that bridges molecular, synaptic, and cellular mechanisms with behavioral control, spanning both the brain and spinal cord. By integrating spinal motor networks with cerebellar and cortical circuits, our research addresses the brain–spinal cord axis as a fundamental determinant of behavior. ​​

• Doctoral theses for medical students
• Bachelor and Master theses for biology and biochemistry students​

Gerstner F, Wittig S, Menedo C, Ruwald S, Carlini MJ, ​Vankova A, Sowoidnich L, ​Martin-Lopez G, ​Dreilich V, Alonso Collado A, Pagiazitis JG, Aousji O, Grzyb C, Smith AK, Yang M, Roselli F, Mentis GZ, Sumner CJ, Pellizzoni L​, Simon CM* (2025).
Cerebellar pathology contributes to neurodevelopmental deficits in spinal muscular atrophy.
Brain awaf336​  *Correspondence

Simon CM*, Delestrée N, Montes J, Sowoidnich L, Gerstner F, Carranza E, Buettner JM, Pagiazitis JG, Prat-Ortega G, Ensel S, Donadio S, Dreilich V, Carlini MJ, Garcia JL, Kratimenos P, Chung WK, Sumner CJ, Weimer LH, Pirondini E, Capogrosso M, Pellizzoni L, De Vivo DC, Mentis GZ​ ​​(2025).
Proprioceptive synaptic​​ dysfunction is a key feature in mice and humans with spinal muscular atrophy.
Brain 148:2797-2811  *Correspondence

Pagiazitis JG, Delestrée N, Sowoidnich L, Sivakumar N, Simon CM, Chatzisotiriou A, Albani M, Mentis GZ​ (202​5).
Catecholaminergic dysfunction drives postural and locomotor deficits in a mouse model of spinal muscular atrophy​​.
Cell Rep 44:115147

Tapken I, Schweitzer T, Paganin M, Schüning T, Detering NT, Sharma G, Niesert M, Saffari A, Kuhn D, Glynn A, Cieri F, Santonicola P, Cannet C, Gerstner F, Faller KME, Huang YT, Kothary R, Gillingwater TH, Di Schiavi E, Simon CM, Hensel N, Ziegler A, Viero G, Pich A, Claus P​ (2025).
The systemic complexity of a monogenic disease: the molecular network of spinal muscular atrophy.​
Brain 148:580-596

Upadhya M, Kirmann T, Wilson MA, Simon CM, Dhangar D, Geis C, Williams R, Woodhall G, Hallermann S, Irani SR, Wright SK​ (2024).
Peripherally-derived LGI1-reactive monoclonal antibodies cause epileptic seizures in vivo. 
Brain 147:2636-2642​

Kong L., Hassinan, C., Gerstner, F., Buettner, J.M., Petigrow, J., Valdivia, D., Chan-Cortés, M., Mistri, A., Cao, A., McGaugh, S.A., Denton, M., Brown, S., Ross, J., Schwab, M., Simon, C.M., Sumner, C. (2023).
Boosting neuregulin 1 type-III expression hastens SMA motor axon maturation.
Acta neuropathol commun 11:53

Hennlein, L., Ghanawi, H., Gerstner, F., Palominos Garcia, E., Yildirim, E., Saal-Bauernschubert, L., Moradi, M., Deng, C., Klein, T., Appenzeller, S., Sauer, M., Briese, M., Simon, C.M., Sendtner, M., Jablonka, S. (2023).
Plastin 3 rescues cell surface translocation and activation of TrkB in spinal muscular atrophy.
J Cell Biol 222:e​20220​4113

Buettner, J.M., Sowoidnich, L., Gerstner, F., Blanco-Redondo, B., Hallermann, S., Simon, C.M. (2022).
p53-dependent c-Fos expression is a marker but not executor for motor neuron death in spinal muscular atrophy mouse models.
Front Cell Neurosci 16:1038​276

Tisdale, S., Van Alstyne, M., Simon, C.M., Mentis, G.Z., and Pellizzoni, L. (2022).
SMN controls neuromuscular junction integrity through U7 snRNP.
Cell Rep 40:111393

Buettner, J.M., Kirmann, T., Mentis, G.Z., Hallermann, S., and Simon, C.M. (2022).
Laser microscopy acquisition and analysis of premotor synapses in the murine spinal
cord.
STAR Protoc 3:101236

Buettner, J.M., Sime Longang, J.K., Gerstner, F., Apel, K.S., Blanco-Redondo, B., Sowoidnich, L., Janzen, E., Langenhan, T., Wirth, B., and Simon, C.M. (2021).
Central synaptopathy is the most​ conserved feature of motor circuit pathology across spinal muscular atrophy mouse models.
iScience 24:103376

Kong, L., Valdivia, D.O., Simon, C.M., Hassinan, C., Delestree, N., Ramos, D., Park J.H., Celeste, P., Xu X., Crowder, M., Gyrzb, C., King, Z., Petrillo, M., Swoboda, K., Davis, C., Lutz, C., Weetall, M., Naryshkin, N., Crawford, T.O., Mentis, G.Z., Sumner, C.J. (2021).
​Impaired prenatal motor axon development necessitates early therapeutic intervention ​in severe SMA.
Sci Transl Med 13:eabb6871

Simon, C.M*., Blanco-Redondo, B., Buettner, J.M., Pagiazitis, J.G., Fletcher, E.V., Sime Longang, J.K., and Mentis, G.Z. (2021).
Chronic Pharmacological Increase of Neuronal Activity Improves Sensory-Motor Dysfunction in Spinal Muscular Atrophy Mice.
J Neurosci 41:376-389  *Correspondence

Simon, C.M., Van Alstyne, M., Lotti, F., Bianchetti, E., Tisdale, S., Watterson, D.M., Mentis, G.Z., and Pellizzoni, L. (2019).
Stasimon Contributes to the Loss of Sensory Synapses and Motor Neuron Death in a Mouse Model of Spinal Muscular Atrophy.
Cell Rep 29:3885-3901

Van Alstyne M, Simon CM, Sardi SP, Shihabuddin LS, Mentis GZ, Pellizzoni L. (2018)
Dysregulation of Mdm2 and Mdm4 alternative splicing underlies motor neuron death in spinal muscular atrophy.
Genes Dev 32:1045-1059

Simon CM, Dai Y, Van Alstyne M, Koutsioumpa C, Pagiazitis JG, Chalif JI, Wang X, Rabinowitz JE, Pellizzoni L, Henderson CE, Mentis GZ (2017)
Converging mechanisms of p53 activation drive motor neuron degeneration in spinal muscular atrophy.
Cell Rep 21:3767–3780

Fletcher EV, Simon, CM, Pagiazitis, JG, Chalif, JI, Vukojicic, A, Drobac, E, Wang, X, and Mentis, GZ (2017)
Reduced sensory synaptic excitation impairs motor neuron function via Kv2.1 in spinal muscular atrophy.
Nat Neurosci 20:905-916

Simon CM, Janas A.M, Lotti F, ​Tabia JC, Pellizzoni L, Mentis GZ (2016)
A stem cell model of the motor circuit uncouples motor neuron death from hyperexcitability induced by SMN deficiency.
Cell Rep 16:1416​​​​–1430

Jesse CM, Bushuven E, Tripathi P, Chandrasekar A, Simon CM, Drepper C, Yamoah A, Dreser A, Katona I, Johann S​​, Beyer C, Wagner S, Grond M, Nikolin S, Anink J, Troost D, Sendtner M, Goswami A, Weis J (2016)
ALS-associated endoplasmic reticulum proteins in denervated skeletal muscle: Implications for motor neuron disease pathology.
Brain Pathol 27:781-794

Mendelsohn AI, Simon CM, Abbott LF, Mentis GZ, Jessell T (2015)
Activity Regulates the Incidence of Heteronymous Sensory-Motor Connections.
Neuron 87:111-123

Simon CM, Gunnersen JM, Rauskolb S, Holtmann B, Drepper C, Braga M, Wiese S, Jablonka S, Puehringer D, Dombert B, Zielasek J, Hoeflich A, Silani V, Wolf E, Kneitz S, Sommer C, Toyka K, Sendtner M (2015)
Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy.
Acta Neuropathol 130:373-387

de Nooij JC, Simon CM, Simon A, Doobar S, Steel KP, Banks RW, Mentis GZ, Bewick GS, Jessell T (2015)
The PDZ-domain protein Whirlin facilitates mechanosensory signaling in mammalian
proprioceptors.
J Neurosci 35:3073-3084

Dombert B, Sivadasan R, Simon CM, Jablonka S, Sendtner M (2014)
Presynaptic localization of Smn and hnRNP R in axon terminals of embryonic and postnatal mouse motoneurons.
PLoS One 9:e110846

Simon CM, Jablonka, S, Ruiz, R, Tabares, L, Sendtner, M (2010)
Ciliary neurotrophic factor-induced sprouting preserves motor function in a mouse model of spinal muscular atrophy.
Hum Mol Genet 19:973-986

Fischer, M, Pereira, PM, Holtmann, B, Simon, CM, Hanauer, A, Heisenberg, M, Sendtner, M (2009)
P90 ribosomal s6 kinase 2 negatively regulates axon growth in motoneurons.
Mol Cell Neurosci 42:134-141

Christian Simon, PhD
Carl-Ludwig-Institute for Physiology Leipzig University,
Liebigstr. 27, 04103 Leipzig, Germany
Room E105
phone: +49 (0) 341 97 15325
email: Christian.Simon@medizin.uni-leipzig.de​