Kontakt

apl. Prof. Dr. rer. nat.
Jochen Kuhse

Gruppenleiter


Medizinische Zellbiologie
Im Neuenheimer Feld 307
69120 Heidelberg
Tel. 06221 54-8663
Email


Gruppe Kuhse

Welcome to our home page describing our research interests in the Kuhse group

Inhibition is a major determinant of brain function

Project 1

γ-aminobutyric acid (GABA) and glycine are the most important inhibitory neurotransmitters in the central nervous system, and are crucially involved in the regulation of responsiveness and excitability in human cortical networks and in the synchronization of cortical neuronal activity by networks of cortical GABAergic interneurons. GABAergic regulation in the CNS plays a central role in a wide range of physiological processes as cognition, memory and learning, motor function and others. Dysfunction in GABAergic signaling is known to be a central factor in the pathogenesis of several neurological disorders.

Cluster formation is regulated by gephyrin

The formation of clusters of inhibitory glycine receptors (GlyR) and some subtypes of GABAA receptors at the postsynaptic membrane strictly requires the scaffold protein gephyrin. However, the molecular mechanisms regulating the precise localization and size of gephyrin and GlyR/GABAA receptor clusters within the somato-dendritic compartments are not completely understood. Collybistin (Cb) is a gephyrin-binding protein and a guanidine exchange factor for the monomeric GTPase Cdc42. We are studying the functional role of Cb and demonstrated that Cb regulates gephyrin phosphorylation at S270 by cyclin-dependent kinases (CDKs) and are currently analyzing the functional implications of this phosphorylation on gephyrin functions.

CDK5 is involved in gephyrin phosphorylation

Cyclin-dependent kinase 5 is a proline-directed serine/threonine kinase and its activity is dependent on the association with neuron-specific regulatory proteins p35 or p39. Interestingly, CDK5 activity was reported to be crucial for neuronal migration, cortex layer formation, neurite outgrowth and retrograde axonal transport. Phosphorylation of various synaptic substrates was shown to have a major impact on pre- and postsynaptic functions of excitatory synapses. For example, analysis of the CDK5-knock-out study revealed that CDK5 loss-of-function in hippocampal circuits results in severe impairments in memory formation and retrival associated with LTP deficits in hippocampal CA1 neurons. Whereas these studies suggest an involvement of CDK5 in the regulation of glutamatergic neurotransmission, almost nothing is known about a putative functional role of CDK5 at inhibitory synapses. We reported that knockdown or inhibition of CDK5 in hippocampal neurons results in reduced phosphorylation of postsynaptic clusters of the scaffold protein gephyrin, detected with the phospho-specific antibody mAb7a. Moreover, CDK5 knockdown or inhibition results in a reduced number of γ2 containing GABAA receptor clusters, suggesting that CDK5 plays an important role at inhibitory synapses. Thus, we are currently studying the functional role of p35 using viral mediated p35 knock-down in cultured hippocampal neurons and are defining the subcellular localization of p35, CDK5, gephyrin and Cb to disclose whether the functional interaction of these proteins take place at postsynaptic membrane specializations or other cellular compartments like endosomes.

Project 2

Alzheimer’s disease and inhibition

Alzheimer’s disease (AD) is incurable and increasing in prevalence in aging populations. Diverse lines of evidence suggest that amyloid-β (Aβ) peptides contribute to AD pathogenesis. Pathological levels of Aβ enhance synaptic depression and impair synaptic plasticity at glutamatergic synapses. The pathogenesis of AD is thought to begin many years before diagnosis and cumulating evidence indicates the involvement of GABAergic neurotransmission in the pathophysiology of AD. We showed a biphasic alteration in expression of gephyrin and GABA(A)Rs in an AD- mouse model (APPPS1), revealing increased expression in early stages (1-3 months) and decreased expression in late (12 months) stages. Moreover, we detected gephyrin as extracellular component of plaques. Thus, gephyrin might be released from neurons and the altered expression of gephyrin might be an early prognostic marker in AD. The robust reduction of gephyrin in aged mice supports the proposed involvement in the pathogenesis of AD and the proposal of gephyrin as an target for AD-treatment. We showed the phosphorylation of gephyrin by CDK5 (P-gephyrin). Interestingly, CDK5 becomes hyperactive in AD and we showed that P-gephyrin and the expression of the CDK5 regulatory protein p35 was increased in the hippocampus at early ages and reduced at later stages. Now, we are addressing three hypothesis: 1: CDK5 and p35 functionally link APP and gephyrin 2: Gephyrin might be a potential early prognostic marker of AD 3: Increase of gephyrin expression in aged APPPS1 mice might be achieved by DHM and artemisinins treatment and might allow to improve AD symptoms Project 2 is supported by Alzheimer Forschung Initiative (2018-2019).

Please contact us if you are interested to work with us contributing to further progress in one of the described projects!

Related Publications

Kiss E, Gorgas K, Schlicksupp A, Groß D, Kins S, Kirsch J, Kuhse J. Biphasic Alteration of the Inhibitory Synapse Scaffold Protein Gephyrin in Early and Late Stages of an Alzheimer Disease Model. Am J Pathol. 2016, 186: 2279-2291

Schwale C, Schumacher S, Bruehl C, Titz S, Schlicksupp A, Kokocinska M, Kirsch J, Draguhn A, Kuhse J. KCC2 knockdown impairs glycinergic synapse maturation in cultured spinal cord neurons. Histochem Cell Biol. 2016, 145: 637-646

O'Sullivan GA, Jedlicka P, Chen HX, Kalbouneh H, Ippolito A, Deller T, Nawrotzki RA, Kuhse J, Kalaidzidis YL, Kirsch J, Schwarzacher SW, Betz H. Forebrain-specific loss of synaptic GABAA receptors results in altered neuronal excitability and synaptic plasticity in mice. Mol Cell Neurosci. 2016, 72: 101-113

Kalbouneh H, Schlicksupp A, Kirsch J, Kuhse J. Cyclin-Dependent Kinase 5 Is Involved in the Phosphorylation of Gephyrin and Clustering of GABAA Receptors at Inhibitory Synapses of Hippocampal Neurons. PLoS ONE. 2014, 9:e104256

Becker M, Kuhse J, Kirsch J. Effects of two elongation factor 1A isoforms on the formation of gephyrin clusters at inhibitory synapses in hippocampal neurons. Histochem Cell Biol. 2013, 140: 603-609

Kuhse J, Kalbouneh H, Schlicksupp A, Mükusch S, Nawrotzki R, Kirsch J. Phosphorylation of gephyrin in hippocampal neurons by cyclin-dependent kinase CDK5 at Ser-270 is dependent on collybistin. J Biol Chem. 2012, 287: 30952-30966

Körber C, Richter A, Kaiser M, Schlicksupp A, Mükusch S, Kuner T, Kirsch J, Kuhse J. Effects of distinct collybistin isoforms on the formation of GABAergic synapses in hippocampal neurons. Mol Cell Neurosci. 2012, 50: 250-259

Dresbach T, Nawrotzki R, Kremer T, Schumacher S, Quinones D, Kluska M, Kuhse J, Kirsch J Molecular architecture of glycinergic synapses. Histochem Cell Biol. 2008, 130: 617-633. Review

Verantwortlich: E-Mail,   Letzte Änderung: Thu, 21.12.2017
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